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Full text of "Haemophilia : recent history of clinical management : the transcript of a witness seminar held at the Wellcome Institute for the History of Medicine, London, on 10 February 1998"

Wellcome Witnesses to 
Twentieth Century Medicine 



Haemophilia: Recent History of 
Clinical Management 



The transcript of a Witness Seminar held at 

the Wellcome Institute for the History of Medicine, 

London, on 10 February 1998 



Volume Four - September 1999 

Witness Seminar Transcript edited by: 

E M Tansey D A Christie 



©The Trustee of the Wellcome Trust, London, 1 999 

First published by the Wellcome Trust, 1999 

The Wellcome Trust is a registered charity, no. 210183. 

ISBN 978 184129 008 9 

All volumes are freely available online at: www.history.qmul.ac.uklresearch/modbiomed/wellcome_witnesses/ 



Please cite as: Tansey E M, Christie DA. (eds) (1999) Haemophilia: Recent history of clinical 
management. Wellcome Witnesses to Twentieth Century Medicine, vol.4. London: 
Wellcome Trust. 



Key 

Front cover photographs, L to R from the top: 

Dr James Matthews 

Professor Stuart Douglas (1921-98), Sir Christopher Booth 

Dr James Matthews, Dr Lise Wilkinson, Mr Ross Dike 

Professor Christine Lee (chair), Mr Clifford Welch 

Professor Christine Lee (chair), Rev'd Alan Tanner 

Professor llsley Ingram (1919-2004), Professor Robert Duthie (1925-2005) 

Mr Clifford Welch, Dr Charles Rizza 

Dr Peter Jones, Dr Ethel Bidwell (d. 2003) 

Back cover photographs, L to R from the top 

Dr Peter Jones, Rev'd Alan Tanner 

Dr Gordon Cook, Dr David Tyrrell (1925-2005), Dr Lise Wilkinson 

Dr Helen Dodsworth, Dr David Evans 

Dr Sheila Howarth (1920-2000) 

Dr Peter Jones, Rev'd Alan Tanner 

Dr David Evans 

Rev'd Alan Tanner, Professor Christine Lee (chair) 



Contents 



Introduction 

E M Tansey 



Haemophilia: Recent History of Clinical Management 

editors : D A Christie and E M Tansey 

Transcript I 

Index 83 



Introduction 



Haemophilia is a rare disorder of the clotting mechanisms of the blood. Estimates 
of its prevalence in the United Kingdom range from 1 in 4000 to 1 in 1 000 of 
the male population. But haemophilia has achieved a prominence out of all 
proportion to its incidence. Several factors have contributed to the reputation of 
the disease: the idea that blood, the very life-carrying force itself, can cause pain, 
incapacity and eventually death, is in itself deeply shocking. So too is the vision of 
small boys suffering the tragic consequences of the disease, added to which is its 
'hidden' transmission through unaffected mothers, and in particular its passage 
via descendants of Queen Victoria through European Royal families. The role of 
the notorious Siberian monk Rasputin, whose ability to 'cure' the Tsarevitch 
Alexey's bleeding led to his sinister involvement with the Russian Royal family, 
may even have contributed to the Russian Revolution. 

This Witness Seminar examined the changes that have occurred in the 
treatment and clinical management of haemophilia in the past half-century, by 
inviting scientists, haematologists, carers and haemophiliacs themselves to a 
meeting at which advances and some of the disastrous reversals of the past 50 
years were discussed. At the end of the second world war, treatment for 
haemophilia had advanced little - immobilization of painfully swollen joints into 
which uncontrolled bleeding took place was the main treatment. Suffering 
children with a short life expectancy were condemned to lie in bed-ridden pain, 
and several Witnesses here recall wards of small boys with limbs in plaster. 
Therapies were limited. Some, like Russell's viper venom, offered limited relief, or 
like Timperley's egg white, held out the hope of relief. For many, the most 
reliable method of treatment was whole blood transfusion, and here one Witness, 
Clifford Welch, himself a sufferer of a mild form of haemophilia, recalls the 
extraordinary situation in which his triplet siblings, all haemophiliacs, frequently 
received life saving transfusions from their mother (page 40). As Welch 
emphasizes, the history of haemophilia during the past 50 years has seen 'an 
extraordinary transformation' (page 76) . 

That extraordinary transformation began in the 1930s, at a time when the 
life expectancy of a haemophiliac was only 20 years. Experimental research and 
laboratory investigations into clotting mechanisms lead to the 'cascade' hypothesis 



See for example Orlando Figes (1996) A People's Tragedy: The Russian revolution, 1891-1924. 
London: Pimlico, 24—34. 



of blood coagulation (see Appendix, page 79) and the identification of a number 
of different clotting factors. The development of blood transfusion services during 
the second world war lead to improvements in fractionation techniques and the 
production of therapeutic plasma for transfusion, although an ominous portent of 
things to come was the recognition of post-transfusion jaundice, transmitted 
through pooled plasma. 

A major breakthrough was made in Oxford in the 1950s when Ethel Bidwell 
first prepared factor VIII concentrate, although its bespoke production meant 
that its availability was limited until the mid 1960s. In the present volume, Dr 
Bidwell and her contemporaries discuss those early days, and the seemingly 
primitive conditions in which blood was collected from local abattoirs, 
transported across Oxford, and then fractionated in poorly equipped labs. 
Photographs of this period (pages 48-51), generously provided by Mr Ross Dike, 
Dr Bidwell's assistant, emphasize not only the makeshift nature of this life-saving 
enterprise, but also the dedication and determination of those involved in this 
pioneering work. 

Isolation of further factors and the involvement of commercial producers and 
the National Blood Transfusion Service all provided increased treatment options 
for haemophiliacs, and the wider availability of cryoprecipitate in the 1 960s lead 
to a further revolution - home treatment pioneered in particular by Kathleen 
Dormandy at the Royal Free Hospital, often in the face of strong disapproval 
from medical colleagues. Home treatment opened up another door to a normal 
life for sufferers and their families. That door to normality was cruelly slammed 
shut by the tragedy, many here use the word scandal, of contamination of blood 
products, many imported because of economy measures, with hepatitis viruses, 
HIV, and even now the spectre of CJD haunts haemophiliacs and their families. 
Haemophilia and the rights of haemophiliacs moved from the purely medical 
arena into the political spotlight as issues of compensation, or recompense (see 
page 65), were successively debated and fought over by pressure groups. The 
effect of litigation against doctors, many of whom had warned Government and 
health authorities of the potential problems of relying on imported blood 
products, adds a particularly poignant flavour to the story, as does the tragedy of 
the devastation of the haemophilic community. One Witness speaks movingly of 
three generations decimated by HIV infection and AIDS (page 66). 
Haematologists and paediatricians had to become rapidly knowledgeable about 
virology and safe sex, the latter an uncomfortable subject to raise in a children's 
hospital (see page 27). 

As well as the straight scientific and clinical advances, other important issues 
emerge from this meeting, some more obvious then others. The setting up of the 
United Kingdom Haemophilia Centre Directors Organization, so that those 



treating this rare condition could benefit from shared experiences, emerged in a 
haphazard way, spearheaded by Rosemary Biggs, who was unable to come to the 
meeting, but who, in a pre-recorded interview told how she organized parties, 
believing that as a woman she could hold a party and not offend anyone, 
although if she called a formal academic meeting feathers might be ruffled. A less 
obvious area for discussion was the impact of material technology, as plastic 
containers, disposable needles and catheters, and ready-made butterfly needles 
improved the preparation and administration of therapeutic products. Some here 
tell harrowing tales of resharpened needles, many so old that they became 
hooked, blocking in the middle of an injection into a deeply distressed child, and 
of a traumatized boy having to be sedated daily to receive life-saving treatment. 

These are just a selection of the issues that are covered here by our Witnesses, 
to whom we are grateful for the time they gave us not only in planning 
and holding this meeting, but also during the editorial process, as we have 
sought to transform a spoken meeting into readable text, and to provide 
explanatory footnotes. 

To date, the Wellcome Trust's History of Twentieth Century Medicine 
Group has held 21 Witness Seminars, most of which have been published, as 
listed in the Table below. For the Haemophilia meeting we are especially grateful 
to Professor Christine Lee for suggesting the subject, assisting us so 
enthusiastically in organizing the meeting, and chairing it so efficiently; Ross 
Dike kindly displayed a selection of his photographs at the meeting and has 
allowed us to reproduce some of them here; and Dr Huw Dorkins kindly read the 
edited transcript for general sense and understandability, and offered suggestions 
for glossary terms. As with all our meetings, we hope that even if the precise 
details of some of the technical sections are not clear to the non-specialist reader, 
the sense and significance of the events are understandable. We are grateful to our 
colleagues in the Wellcome Trust for their help in running these meetings, and 
wish to mention in particular the assistance of the Audiovisual Department, the 
Medical Photographic Library, and the Publishing Department, especially Julie 
Wood who has supervised the design and production of the published volume. 
Mrs Jaqui Carter is our transcriber, and Mrs Wendy Kutner and Mrs Lois 
Reynolds assist us in running the meetings. Finally we thank the Wellcome Trust 
for supporting this programme. 



Tilli Tansey 

Wellcome Institute for the History of Medicine 



Tansey, E M. (ed.) (1998) Witnessing medical history: an interview with Dr Rosemary Biggs, 
conducted by Professor Christine Lee and Dr Charles Rizza. Haemophilia 4: 769-777. 



ill 



History of Twentieth Century Medicine Witness Seminars, 1993-1999 



1993 Monoclonal antibodies 

Organizers: Dr E M Tansey and Dr Peter Catterall 

1 994 The early history of renal transplantation 

Organizer: Dr Stephen Lock 
Pneumoconiosis of coal workers 

Organizer: Dr E M Tansey 

1995 Self and non-self: a history of autoimmunity 

Organizers: Sir Christopher Booth and Dr E M Tansey 

Ashes to ashes: the history of smoking and health 

Organizers: Dr Stephen Lock and Dr E M Tansey 

Oral contraceptives 

Organizers: Dr Lara Marks and Dr E M Tansey 

Endogenous opiates 

Organizer: Dr E M Tansey 

1996 Committee on Safely of Drugs 

Organizers: Dr Stephen Lock and Dr E M Tansey 

Making the body more transparent: the impact of 

nuclear magnetic resonance and magnetic resonance imaging 

Organizer: Sir Christopher Booth 



3 Published in Tansey E M, Catterall P P, Christie D A, Willhoft S V, Reynolds L A. (1997) (eds) 
Wellcome Witnesses To Twentieth Century Medicine, vol. 1. London: Wellcome Trust, 135pp. 

P D'Arcy Hart, edited and annotated by E M Tansey. (1998) Chronic pulmonary disease in South 
Wales coalmines: An eye-witness account of the MRC surveys (1937-1942). Social History of Medicine 
11:459^68. 

Lock S P, Reynolds L A, Tansey E M. (eds) (1998J Ashes to Ashes - The history of smoking and 
health. London: Wellcome Trust, 198-220. 

Published in Tansey E M, Christie D A, Reynolds L A. (eds) (1998) Wellcome Witnesses to 
Twentieth Century Medicine, vol. 2. London: The Wellcome Trust, 282 pp. 



IV 



1997 Research in General Practice 

Organizers: Dr Ian Tait and Dr E M Tansey 

Drugs in psychiatric practice 

Organizers: Dr E M Tansey and Dr David Healy 

The MRC Common Cold Unit 6 

Organizers: Dr David Tyrrell and Dr E M Tansey 

The first heart transplant in the UK 

Organizer: Professor Tom Treasure 

1998 Haemophilia: recent history of clinical management 

Organizers: Dr E M Tansey and Professor Christine Lee 

Obstetric ultrasound: historical perspectives 

Organizers: Dr Malcolm Nicolson, Mr John Fleming and Dr E M Tansey 

Post-penicillin antibiotics 

Organizers: Dr Robert Bud and Dr E M Tansey 

Clinical research in Britain, 1950-1980 

Organizers: Dr David Gordon and Dr E M Tansey 

1999 Intestinal absorption 

Organizers: Sir Christopher Booth and Dr E M Tansey 

The MRC Epidemiology Unit (South Wales) 

Organizers: Dr Andy Ness and Dr E M Tansey 

Neonatal intensive care 

Organizers: Professor Osmund Reynolds, Dr David Gordon and Dr E M Tansey 

British contribution to medicine in Africa after the second world war 

Organizers: Dr Mary Dobson, Dr Maureen Malowany, Dr Gordon Cook and 
Dr E M Tansey 



7 Tansey E M, Reynolds L A. (eds) (1999) Eady heart transplant surgery in the UK. 
Wellcome Witnesses to Twentieth Century Medicine, vol. 3. London: The Wellcome Trust, 72 pp. 
Tansey E M, Christie D A. (eds) (1999) Haemophilia: Recent history of clinical management. 
Wellcome Witnesses to Twentieth Century Medicine, this volume. 



Haemophilia: Recent History of Clinical 

Management 

The transcript of a Witness Seminar held at the Wellcome Institute 
for the History of Medicine, London, on 10 February 1998 

Edited by D A Christie and E M Tansey 



Haemophilia: Recent History 
of Clinical Management 



Participants 

Dr Derek Bangham 

Dr Ethel Bidwell 

Sir Christopher Booth 

Dr Brian Colvin 

Dr Angela Dike 

Mr Ross Dike 

Dr Helen Dodsworth 

Professor Stuart Douglas* 

Professor Robert Duthie 

Dr David Evans 

Dr Sheila Howarth 



Professor Ilsley Ingram 

Dr Peter Jones 

Professor Christine Lee (Chair) 

Dr James Matthews 

Mrs Riva Miller 

Dr Charles Rizza 

Rev Alan Tanner 

Dr Tilli Tansey 

Professor Edward Tuddenham 

Dr David Tyrrell 

Mr Clifford Welch 



Others present at the meeting: Dr Trevor Barrowcliffe, Ms Jacqui 

Marr, 

Dr J K Smith, Miss Rosemary Spooner 

Apologies: Professor Jean-Pierre Allain, Dr Donald Bateman, Dr Rosemary 
Biggs, Mrs Peggy Britten,** Professor Judith Chessells, Dr Audrey Dawson, 
Mr Ron Hutton, Professor Ralph Kekwick, Professor Sir David Weatherall 

*Deceased 15 November 1998 
**Deceased 1 March 1999 



Haemophilia: Recent history 



Professor Christine Lee: 1 I think haemophilia is one of the best areas of 
clinical medicine where we have seen a very rapid introduction of scientific 
discovery into clinical practice. All of us who work on haemophilia realize that 
this has gone on very much with cooperation between the patients and the 
scientists and the doctors. I first saw haemophilia in 1967 when I was a medical 
student in Oxford and we were doing our orthopaedics at the Nuffield 
Orthopaedic Hospital. I have a very clear memory of a ward of little boys with 
their legs strung up, their arms strung up, and I think there was a schoolroom 
nearby. It was with great pleasure that last week we were able to talk with Dr 
Rosemary Biggs, who with Macfarlane, put haemophilia care on the map in 
Oxford from the late 1940s onwards. 3 Unfortunately, Dr Biggs wasn't able to 
be with us today, but I am hoping that throughout the discussions this afternoon 
I can interject some of her comments, and try and raise memories from you and 
our invited speakers. What I am going to try very hard to do - I do have a kind 



1 Professor Christine Lee FRCP FRCPath DSc(Med) (b. 1943) qualified from the University 
of Oxford Medical School and has been Professor of Haemophilia and Director and 
Consultant Haematologist at the Haemophilia Centre and Haemostasis Unit, The Royal Free 
Hospital, London, since 1987 and is a member of the International Society of Thrombosis & 
Haemostasis. She has published many papers on the side-effects of blood product therapy in 
haemophilia, particularly hepatitis and acquired immune deficiency syndrome (AIDS). 

2 Dr Rosemary Biggs MD FRCP (b. 1912) first joined Gwyn Macfarlane in Oxford in 1945 
in his studies on fibrinolysis. She is co-author on many papers including the seminal paper on 
Christmas disease (see for example notes 3, 17, 18, 23, 37 and 198). When the Medical Research 
Council Blood Coagulation Unit in Oxford closed in 1967, Dr Biggs became Director of the 
newly opened Haemophilia Centre. She was Secretary of the UKHCDO from 1968 to 1977. 
See Tansey E M. (ed.) (1998) Witnessing medical history: an interview with Dr Rosemary 
Biggs, conducted by Professor Christine Lee and Dr Charles Rizza. Haemophilia 4: 769-777 '. 

3 Professor R G Macfarlane CBE FRCP FRCPS FRS (1907-1987) qualified in medicine 
from St Bartholomew's Hospital in 1933 and in 1936 he became Clinical Assistant 
Pathologist at the Postgraduate Medical School Hammersmith. He was appointed clinical 
pathologist to the Radcliffe Infirmary, Oxford in 1940 and was Radcliffe lecturer in 
haematology in 1943. He was joined by Dr Rosemary Biggs (see note 2 above) and Dr Ethel 
Bidwell (see note 47 below) and together they collaborated closely on extensive studies of 
fibrinolysis and purification and concentration of the various blood-clotting factors. He 
became Director of the Blood Coagulation Research Unit in Oxford in 1959, Fellow of All 
Souls College, Oxford, in 1963, Professor of Clinical Pathology in the University of Oxford 
in 1965, and President of the Haemophilia Society in 1981. The Macfarlane Trust was 
established in his memory to administer funds to haemophiliacs infected with HIV through 
treatment with blood products. See Born G V R, Weatherall D J. (1990) Robert Gwyn 
Macfarlane. Biographical Memoirs of Fellows of the Royal Society 35: 211-239. Robb-Smith A 
(1993) Life and Achievements of Professor Robert Gwyn Macfarlane FRS Pioneer in the Care of 
Haemophiliacs. London: Royal Society of Medicine Services Limited. See also Biggs R. (1967) 
Thirty years of haemophilia treatment in Oxford. British Journal of Haematology 13: 452-463. 



Haemophilia: Recent history 

of programme here, but I am told by Dr Tansey that these things tend to go off 
in ways which nobody can predict - is to try by the end of the afternoon to have 
covered the introduction of treatment and the organization of haemophilia, and 
to talk a bit about some of the disastrous side-effects and the impact that that 
has had on us all. So without going on any more, I am going to start by asking 
Ilsley Ingram, who was Professor of Experimental Haematology at St 
Thomas' Hospital, and has an amazing history to tell us, and perhaps, Ilsley, 
you could begin a bit at the beginning and talk about when you first got into 
haemophilia. 

Professor Ilsley Ingram: 4 I have made a note of some landmarks in the 
history of haemophilia. 5 The earliest known written reference to abnormal post- 
traumatic bleeding in maternally-related males is from rabbinical references 
from the second century to do with circumcision. The earliest clear medical 
description of haemophilia is probably in 1803, and the name 'haemophilia' is 
first found in a dissertation by Hopff in 1828. Haemarthroses were not clearly 
described in relation to haemophilia until 1890, because before that they were 
thought to be rheumatic manifestations. The first female haemophiliac, from a 
first-cousin marriage, is believed to be that recorded by Treves in 1886; and 
the diagnostic triad of lifelong, male bleeding, transmitted by females, is first 
really brought out in the monumental study of Bulloch and Fildes in 1911. 
They analysed the entire previous literature on abnormal bleeding and sorted 
out the reports they thought were probably to do with haemophilia, and 
published a large number of family trees. We all know about Queen Victoria, 
who had a haemophilic son, Leopold, born in 1853, and two carrier daughters 
who transmitted the abnormal gene to the Royal Houses of Spain and Russia. 
Defective blood clotting in haemophilia was first noted, I think, by Wardrop 
in 1835, yet haemophilic blood was normally clotted by thrombin by Addis in 
1910 and the normal prothrombin time was recorded by Quick in 1935. 

I always regard that as the beginning of the modern period in the study of 
haemophilia, because up to that time, although some plasma fractions were 
made in the laboratories, it was thought that it was the prothrombin that was 
abnormal in haemophilia. A globulin fraction of plasma was found to correct 



4 Professor Ilsley Ingram FRCP FRCPath FLS (b. 1919) was Director of the Haemophilia 
Centre at St Thomas' Hospital from 1956 to 1979, and Professor of Experimental 
Haematology in the University of London at St Thomas's Hospital Medical School from 1972 
to 1979. 

5 These early landmarks in the history of haemophilia are detailed and referenced in Ingram G 
I C. (1997) The history of haemophilia. Haemophilia 3: 5-15. idem (1976) The history of 
haemophilia. Journal of Clinical Pathology 29: 469-479. 



Haemophilia: Recent history 

the haemophilic blood-clotting defect by Patek and Taylor in 1937, 6 so in the 
1930s the modern study had begun. The term 'antihaemophilic globulin' 
(AHG) was coined by Lewis, Taylor and others in 1946. 7 In 1950 Merskey 
described mild haemophilia with a normal whole blood-clotting time in a 
glass tube. 8 This was of great clinical importance because up until then it was 
thought that if the clotting time was normal, the person could not have 
haemophilia. But we know that mild haemophiliacs do indeed have serious 
post-traumatic bleeding, for instance if they are inadvertently operated on 
without proper preparation. 

From 1951 onwards there were early assay methods for factor VIII, 
particularly Merskey and Macfarlane [in Oxford] , and Graham and others in 
America. 9 Roman numerals were first used to designate clotting factors by a 
committee chaired by Wright in 1962; 10 and the immunological detection of 
factor VIII was begun by Ratnoff and others in 1971, n who showed that 
haemophilic plasma, although it contained no factor VIII activity, reacted with 
a rabbit antibody to human factor VIII. I expect that subsequent speakers will 
say more about the immunological side, because that has developed greatly 
since I retired in 1979. An international standard for factor VIII clotting 
activity was developed in the 1960s by the Biological Standards Division of 
the National Institute for Medical Research; and the Division began to 
distribute working standards to clinical laboratories. 13 

Von Willebrand's disease was distinguished from haemophilia by von 
Willebrand in 1926 and by Minot in 1928, and was shown to affect both sexes 



6 Patek A J, Taylor F H L. (1937) Hemophilia II. Some properties of a substance obtained 
from normal human plasma effective in accelerating the coagulation of hemophilic blood. 
Journal of Clinical Investigation 16: 113-124. 

7 Lewis J H, Tagnon H J, Davidson C S, Minot G R, Taylor F H L. (1946) The relation 
of certain fractions of the plasma globulins to the coagulation defect in hemophilia. 
Blood 1: 166-172. 

8 Merskey C. (1951) Haemophilia associated with normal coagulation time. British Medical 
Journal i: 906-912. See biographical note 35 below. 

9 Merskey C, Macfarlane R G. (1951) Female carrier of haemophilia: a clinical and laboratory 
study. Lancet i: 487-490. Graham J B, Penick G D, Brinkhous K M. (1951) Utilization of 
antihemophilic factor during clotting of canine blood and plasma. American Journal of 
Physiology 164: 710-715. 

10 Irving Wright, Professor of Internal Medicine at Cornell, New York, chaired the 
International Committee on Blood Clotting Factors, which later became the International 
Committee on Haemostasis and Thrombosis in 1965. See Wright I S. (1962) The nomenclature 
of blood clotting factors. Thrombosis et Diathesis Haemorrhagical ': 381-388. 

11 Zimmerman T S, Ratnoff O D, Littell A S. (1971) Detection of carriers of classic 
hemophilia using an immunologic assay for antihemophilic factor (factor VIII). Journal of 
Clinical Investigation 50: 255-258. 

12 The patient's plasma and the antibody diffuse in a gel: where they meet, an opaque line forms 
if the plasma contains a substance 'recognized' by the antibody. 

13 See Dr Derek Bangham's contribution on page 20. 



Haemophilia: Recent history 

and to have a long bleeding time. Reduced levels of factor VIII were also 
found in von Willebrand's disease by Alexander and Goldstein in 1953, and by 
Larrieu and Soulier in 1953. 15 

In 1944 Pavlovsky described the mutual cross-correction of two 
haemophilic bloods 16 and this led to the identification of factor IX deficiency 
with identical clinical manifestations to haemophilia. Then Macfarlane and 
Biggs developed the thromboplastin generation test which allowed clinical 
laboratories to distinguish the two conditions. 17 It was largely on that basis, I 
understand, that the system of 'Haemophilia Centres' was set up in Britain, the 
initial purpose being to separate the diagnosis of haemophilia from that of 
Christmas disease (factor IX defect), 18 in readiness for the time when different 
specific treatments would be available. Topical treatment with Russell's viper 
venom [Stypven], which was found to clot haemophilic blood, at the dilution of 
one in a million, was identified by Macfarlane in 1934. 19 Use of blood 
transfusion, interestingly, dates back to the work of Lane in 1840, who 
effectively administered the blood of someone he described as 'a stout young 
woman' to a boy, known to have bled abnormally, who had been inadvertently 
operated on, and bled and bled. 



14 See Willebrand E A von. (1926) Hereditare pseudohemofili. Finska Lakaresallskapets 
Handlingar 68: 87-112. Minot G R. (1928) Familial hemorrhagic condition associated with 
prolongation of bleeding time. American Journal of Medical Science \7 5: 301-306. 

15 Alexander B, Goldstein R. (1953) Dual hemostatic defect in pseudohemophilia. Journal of 
Clinical Investigation 32: 551. Larrieu M J, Soulier J P. (1953) Deficit en facteur 
antihemophilique A chez une fille, associe a un trouble du saignement. Revue d'hematologie 8: 
361-370. idem Differentiation of hemophilia into 2 groups: study of 33 cases. New England 
Journal of Medicine 2A9: 547-553. 

16 Professor Ilsley Ingram added: 'Both having prolonged clotting times but the mixture 
clotting normally, showing that the samples corrected each other and must therefore have had 
different deficits, each able to provide what the other lacked.' Letter to Dr Daphne Christie, 13 
March 1999. See CastexM R, Pavlovsky A, Simonetti C. (1944) Contribucion al estudio de la 
fisiopatogenia de la hemofilia. Medicina Buenos Aires 5: 16—24. Pavlovsky A (1947) 
Contribution to the pathogenesis of hemophilia. Blood 2: 185-191. 

17 Macfarlane R G, Biggs R. (1953) Thrombin generation test: application in haemophilia and 
thrombocytopenia. Journal of Clinical Pathology 6: 3-8. Biggs R, Douglas A S. (1953) 
Thromboplastin generation test. ibid. 23-29. Biggs R, Douglas A S, Macfarlane R G. (1953) 
Formation of thromboplastin in human blood. Journal of Physiology 119: 89-101. 

18 See Biggs R, Douglas A S, Macfarlane R G, Dacie J V, Pitney W R, Merskey C, O'Brien J R. 
(1952) Christmas disease: a condition previously mistaken for haemophilia. British Medical 
Journal ii: 1378-1382. 

19 Macfarlane R G, Barnett B. (1934) The haemostatic possibilities of snake venom. Lancet ii: 
985-987. idem On the relative potency of certain snake-venoms to coagulate haemophilic 
blood. Proceedings of the Zoological Society 4: 977-978. Macfarlane R G. (1965) Russell's viper 
venom, 1934-64. Oxford Medical School Gazette \7: 100-115. 

20 Lane S. (1840) Haemorrhagic diathesis. Successful transfusion of blood. Lancet i: 185-188. 
See also Ingram G I C. (1995) Mr Lane and the blood of a stout young woman. Haemophilia 

1:277-282. 



Haemophilia: Recent history 

In 1931 Macfarlane, who reviewed the previous treatments offered for 
haemophilia, clearly recognized that human blood transfusion was the only 
effective systemic treatment. Freeze-dried fractions made from human blood 
were developed in the 1950s by Kekwick and Wolf, Soulier, Blomback and 
others, 22 and then Dr Bidwell in 1954 introduced the fractions from ox and pig 
plasma. 23 In 1965 Judith Pool introduced cryoprecipitate. 2 This was a major 
clinical advance because of the convenience of the smaller volume for 
administration and because it could be stored frozen. Use of antifibrinolytic 
drugs to spare factor VIII doses was introduced by Walsh in 1 97 1 in connection 
with dental extractions, 25 and the use of l-deamino-8-D-arginine vasopressin 
(DDAVP) in mild haemophilia and von Willebrand's disease by Mannucci in 
1977. 26 

I will add that in the UK the Haemophilia Society had its roots in the 
1930s, curiously when Macfarlane and J B S Haldane worked together on the 
interesting parallel between the inheritance of haemophilia and red/green colour 
blindness. 27 That was probably the first time in Britain that haemophiliacs 
came together and so met one another. In 1950 the British Haemophilia 
Society, which had at first grandly been called the International Haemophilia 



21 Macfarlane R G. (1931) Haemophilia: a short survey. St Bartholomew's Hospital Journal 
39: 47-54. 

22 Kekwick R A, Wolf P. (1957) A concentrate of human antihaemophilic factor — its use in six 
cases of haemophilia. Lancet'v. 647-650. Soulier J P, Gobbi F, Larrieu M J. (1957) Separation 
du fibrinogene et du factuer antihemophilique A Revue d'hematologie 12: 481-496. Blomback 
B, Blomback M, Nilsson I M. (1958) Note on the purification of human antihemophilic 
globulin. Acta Chemica Scandinavica 12: 1878. 

23 Macfarlane R G, Biggs R, Bidwell E. (1954) Bovine antihaemophilic globulin in the 
treatment of haemophilia. Lancet'v. 1316-1319. Bidwell E. (1955) The purification of bovine 
antihaemophilic globulin. British Journal of Haematology 1: 35 and 386. 

24 Professor Judith Pool reported that on slowly thawing frozen plasma, much of the factor 
VIII activity remained with the fibrinogen sludge which was slow to re-dissolve, the so-called 
'cryoprecipitate'. This could be spun down, re-frozen for storage and finally reconstituted for 
administration in a small volume of saline. For details see Pool J D, Shannon A E. (1965) 
Production of high-potency concentrates of antihemophilic globulin in a closed bag system. 
New England Journal of Medicine 2T5: 1443-1447. See also Sibinga C S. (1996) Emile Remigy 
and the discovery of anti-haemophilic activity in cryoprecipitate. Haemophilia 2: 56-60. 

25 Walsh P N, Rizza C R, Matthews J M, Eipe J, Kernoff P B A, Coles M D, Bloom A L, 
Kaufman B M, Beck P, Hanan C M, Biggs R. (1971) Epsilon-aminocaproic acid therapy for 
dental extractions in haemophilia and Christmas disease: a double blind controlled trial. 
British Journal of Haematology 20: 463-475 . 

26 See Cash J D, Gader A M A, Da Costa J. (1974) The release of plasminogen activator and 
factor VIII to lysine vasopressin, arginine vasopressin, l-deamino-8-D-arginine vasopressin, 
angiotensin and oxytocin in man. British Journal of Haematology 27: 263-264. Mannucci P M, 
Ruggeri Z M, Pareti F I, Capitanio A (1977) l-deamino-8-D-arginine vasopressin: a new 
pharmacological approach to the management of haemophilia and von Willebrand's disease. 
Lancet'v. 869-872. 

27 See Bell J, Haldane J B S. (1937) Linkage between genes for colour-blindness and 
haemophilia in man. Proceedings of the Royal Society B 123: 1 19-150. 



Haemophilia: Recent history 

Society, was registered as a charity; the World Federation of Hemophilia was 
started in 1963. 

Haemophiliacs have always been very generous in giving their plasma for 
experimental work as a quid pro quo for being looked after. I think that this is a 
very interesting example of the way that affected people and their doctors 
worked together for mutual benefit. 

Lee: I would like to pursue some of the things you brought up there. When we 
were talking with Dr Biggs last week, 28 she was laying great emphasis on the 
thromboplastin generation test 29 as the point at which diagnosis was possible. 
Would you agree with that? 

Ingram: Yes, in Britain, I think that was of great importance. In America, at 
Chapel Hill, Brinkhous and Graham developed the partial thromboplastin 
time, 30 which wasn't so good at distinguishing deficiencies of factors VIII and 
IX, but could be adapted to do so by the use of appropriate plasmas. But the 
great thing about the thromboplastin generation test was that the reagents were 
made from normal plasma, so that you didn't have to have the haemophilic 
blood there to show whether or not it was corrected. I will go back to the time 
where the mutual correction of two apparently haemophilic plasmas led to the 
realization that there was more than one defect, because, after all, this is 
analogous to the general biological principle of identification from type 
specimens. There you had a type specimen of haemophilic blood and then you 
saw whether other bloods would correct it or not. Fortunately, the 
thromboplastin generation test side-stepped that and made it unnecessary for 
all laboratories to have samples of both haemophilic and Christmas disease 
plasma always on hand. 

Lee: And that mutual correction, when we were talking with Dr Biggs, 31 she 
said was just done by accident. 



28 See note 2 above. 

29 See note 17 above. 

30 Langdell R D, Graham J B, Brinkhous K N. (1950) Prothrombin utilization during 
clotting: comparison of results with 2-stage and 1 -stage methods. Proceedings of the Society for 
Experimental Biology and Medicine 74: 424. Langdell R D, Wagner R H, Brinkhous K M. 
(1951) 

Effect of antihemophilic factor on one-stage clotting tests: presumptive test for hemophilia 
and a simple one-stage antihemophilic assay procedure. Journal of Laboratory and Clinical 
Medicine 
41: 637-647. 

31 See note 2 above. 



Haemophilia: Recent history 

Ingram: I think it was, yes. It was a bit of serendipity. 

Lee: When the thromboplastin generation test was described and it was 
possible to differentiate, who was using it? Was it just the very specialized 
centres, or was it more widespread? 

Ingram: I think it gradually spread, although perhaps people who hadn't seen 
it done found it rather fiddly to do from written instructions, but it was 
becoming more widely used. 

Lee: I think it might be an appropriate time to talk about differentiation of 
factor VIII and factor IX. Dr Rizza, remind us about Christmas disease. 

Dr Charles Rizza: 32 Can I go back to what Professor Ingram said? I think of 
the serendipity when Stephen Christmas first came to Oxford: I think it was 
John Poole 33 who did the mixing experiments. He took haemophilic blood and 
mixed it with Stephen Christmas's blood and, lo and behold, it was corrected, 
and they thought, 'What is going on here? There is something different'. That 
was how it all began. But Stuart Douglas, I think, was there at the time and that 
was 

what encouraged him to look further and use the thromboplastin generation test 
in 1951/52. 

Professor Stuart Douglas: 34 I want to comment on the contribution of 
experiments on mixing of bloods from two haemophiliacs. We should 



32 Dr Charles Rizza FRCPEd (b. 1930) was MRC Clinical Research Fellow at the Blood 
Coagulation Research Unit in Oxford between 1958 and 1961, working with Dr R G 
Macfarlane and Dr Rosemary Biggs. He was awarded an MD from the University of St 
Andrews in 1962 and received the University Gold Medal for his thesis 'Conditions affecting 
the level of antihaemophilic globulin (factor VIII) in the blood.' He was Consultant 
Physician at the Oxford Haemophilia Centre from 1966 to 1993, and Director of the Centre 
from 1977 to 1993. He was Clinical Lecturer in Haemophilia at the University of Oxford 
between 1967 and 1993 
and Chairman of the United Kingdom Haemophilia Centre Directors Organization from 
1987 to 1990. 

33 John Poole was a registrar in Oxford in 1951. See also note 41. 

34 Professor Stuart Douglas FRCP FRSEd (1921-1998) qualified in medicine at Glasgow in 
1944. He won a Medical Research Council fellowship to work in the Blood Coagulation 
Research Unit in Oxford where he and others devised the thromboplastin generation test (see 
note 17 above). His main interest was in the study of blood coagulation and bleeding, and later 
problems of thrombosis. He was Professor of Medicine in Aberdeen, from 1970 to 1985 
(Emeritus). 



Haemophilia: Recent history 

recognize Clarence Merskey, a research fellow from South Africa working in 
Oxford in 1949, for introducing the habit of mixing blood from two 
haemophiliacs. He pointed out that there were at least two grades of 
haemophilia: one severe and one mild. 3 Addition of a small amount of plasma 
from the mild patient would give some correction of the plasma-clotting time 
of the severe haemophiliac, 

but not as effectively as normal plasma. This mixing became part of the 
laboratory 'work up' of a new suspected bleeder. A test for haemophilia was 
failure to correct the recalcification time of a known haemophilic plasma as 
effectively as normal plasma. 37 

I thought of the Oxford-taught investigators, John Poole was the first to 
find cross-correction. 38 I did not know that John O'Brien had found this at an 
earlier date. 39 



Ingram: I think even before the mixing in Oxford someone did it in South 
America. 



Rizza: Pavlovsky 



40 



Douglas: I think if you look, John Poole didn't actually describe that 
phenomenon until the Christmas disease paper was published, but I think if 
you talk to him, you'll find that he did it many years earlier. Ilsley Ingram in 



35 Dr Clarence Merskey FRCP (1914-1982) worked with Biggs and Macfarlane from 1949 to 
1951 at the Radcliffe Infirmary, Oxford, where he developed his coagulation expertise and 
made valuable contributions to the study of haemophilia. In New York he collaborated closely 
with Alan Johnson (mentioned later in the meeting) devising tests for measuring fibrin 
degradation products. See also notes 8, 9 and 36. 

36 Merskey C. (1950) The laboratory diagnosis of haemophilia. Journal of Clinical Pathology 
3: 301-320. See also note 8 above. 

37 Small amounts of normal plasma and of the patient's plasma are added to citrated plasma 
from the known haemophiliac, and the clotting times after recalcification are recorded. Very 
small proportions of normal plasma will shorten the calcium-clotting time of haemophilic 
plasma almost to normal. If similar proportions of the patient's plasma fail to do so, he 
presumably has haemophilia. See Biggs R, Macfarlane R G. (1953) The coagulation defect in 
haemophilia. In Human Blood Coagulation and its Disorders, ch XV. Oxford: Blackwell 
Scientific Publications, 227-231, 348. 

38 See notes 16 and 41. 

39 Professor Stuart Douglas wrote: 'I had thought the first assessment in Oxford of Stephen 
Christmas's blood was a sample collected by me from London at the request of John Dacie and 
Bob Pitney in 1952. I am willing to be proved wrong.' Letter to Dr Tilli Tansey, 24 July 
1998. 

op. cit. note 16 above. 

41 Poole J C F. (1953) A haemorrhagic state resembling haemophilia. Lancet i: 122. op. cit. 
note 18 above. 



10 



Haemophilia: Recent history 

his introductory remarks also mentioned Mannucci in relation to the use of 
DDAVP in mild haemophilia. 42 There was an important British contribution 
which led to the work by Mannucci in 1977. You [Ingram] showed that the level 
of factor VIII in normal blood could be raised by injections of adrenaline 43 
and you [Rizza] showed a rise in factor VIII after exercise. John Cash and his 
colleagues in Edinburgh showed that these responses could not be totally 
prevented by OC and (3 receptor blockers and the possibility was raised of an 
involvement of the hypothalamic-pituitary axis as a secondary pathway. 5 The 
only neuropeptide available for human prescription was vasopressin - 
antidiuretic hormone 

(ADH) - and they gave this to themselves, and found a factor VIII response; 
side-effects were too troublesome for clinical practice (vasoconstriction, and 
powerful contractions of the uterus and gastrointestinal tract). They found that 
the synthetic analogue desmopressin [DDAVP] was as active in raising factor 
VIII (and von Willebrand's factor) as the natural antidiuretic hormone. 
Clinicians in their Haemophilia Centre in Edinburgh had ethical doubts about 
trying this in haemophilia. The clinical value was then established by Mannucci. 

Ingram: Desmopressin [DDAVP] is a synthetic analogue of vasopressin 
[antidiuretic hormone] from the hypothalamic/posterior pituitary axis; it has 
the advantage that it does not stimulate bowel contraction or raise blood 
pressure like the normal hormone, so that it can be given virtually 
symptomlessly, but it does raise factor VIII between two- and four-fold in the 
normal subject and proportionally in mild haemophilia but not in severe 
haemophilia. It has also found a place in treating von Willebrand's disease and 
thrombocytopenia. 

Lee: We still use it by preference in people with mild disease, rather than 
clotting factor concentrates, and recently there is a formulation which comes as 
a nasal spray which people are using for home treatment as well. Charlie, can we 
get back to Christmas disease and 1952? 



2 op. cit. note 26 above. 

3 Ingram G I C. (1961) Increase in antihaemophilic globulin activity following infusion of 
adrenaline. Journal of Physiology 156: 217-224. 

Rizza C R. (1961) Effect of exercise on the level of antihaemophilic globulin in human 
blood. Journal of Physiology 156: 128-135. 

45 Ingram G I C, Vaughan Jones R. (1966) The rise in clotting factor VIII induced in man by 
adrenaline: effect of a- and [3-blockers. Journal of Physiology 187: 447-454. Gader A M, Da 
Costa J, Cash J D. (1974) The effect of propranolol, alprenolol and practolol on the 
fibrinolytic and factor VIII responses to adrenaline and salbutamol in man. Thrombosis 
Research A: 25-33. 

46 Mannucci P M, Ruggeri Z M, Pared F I, Capitano A. (1983) op. cit. note 26 above. 

11 



Haemophilia: Recent history 

Rizza: Dr Bidwell is here. She is the one to answer that. 

Dr Ethel Bidwell: 47 I couldn't think what everybody was so interested in, in 
1952, and they weren't at all interested in what I was doing. Then people 
slowly explained to me about this Christmas disease and then I realized. 

Rizza: I think the trouble with Christmas disease in 1952 was that, as for 
haemophilia, there was no therapy. There was no treatment apart from plasma 
transfusion, giving moral support and holding the patient's hand. When the 
NHS began 50 years ago, that's just when I started to study medicine, there 
was no therapy, although as Ilsley said, the antihaemophilic globulin had been 
recognized as being the important constituent of plasma which haemophiliacs 
lack. Since 1941, Cohn had been fractionating human plasma into its various 
constituents, 48 so rather than giving the patient the whole plasma the different 
patients were given only the fraction they required. It was soon shown that 
Cohn's fibrinogen fraction was contaminated with factor VIII and began to 
be used in a limited way in the late 1940s and early 1950s for the treatment 
of haemophilia. 

Bidwell: Certainly for a long time after that we weren't still sure that factor 
VIII and fibrinogen were not modified forms of the same thing. One of the 
few purely academic things that I was ever involved in was electrophoretic 
separation, not from the point of view of preparation of factor VIII, but just to 
show you could get them apart. 

Lee: Dr Bidwell, tell us when you first got involved in making treatment for 
haemophiliacs. 



7 Dr Ethel Bidwell (b. 1919), an experienced enzyme chemist, joined Macfarlane in Oxford 
in 1950 and in 1952 started a study of plasma concentration and selective extraction of factor 
VIII. By 1953 she was producing a concentrated bovine factor VIII 8000 times as strong as 
normal human plasma. In 1959 she held a full time MRC appointment in the newly opened 
MRC Blood Coagulation Research Unit in the grounds of the Churchill Hospital, 
Headington, Oxford, and concerned herself with the preparation of human coagulation factors. 
See Report of the Medical Research Council for the Year 1958-1959. London: HMSO, 111. Her 
research assistant, Ross Dike (see biographical note 177 below), joined the team in 1954. Dr 
Bidwell retired in 1981. See also notes 60 and 62 below. 

8 Cohn E J. (1941) Properties and functions of plasma proteins with consideration of methods 
for their separation and purification. Chemical Reviews 28: 395-417. idem (1947) Separation of 
blood into fractions of therapeutic value. Annals of Internal Medicine 2.6: 341-352. 

9 Human factor VIII was first available in 1957, see note 3 above. For animal factor VIII, see 
page 13 below. Minot G R, Taylor F H L. (1947) Hemophilia: the clinical use of 
antihemophilic globulin. Annals of Internal Medicine 26: 363-367. Alexander B, Landwehr G. 
(1948) Studies of hemophilia. II. The assay of the antihemophilic clot promoting principle in 
normal human plasma with some observations on the relative potency of certain plasma 
fractions. Journal of Clinical Investigation 27: 9-18. 



12 



Haemophilia: Recent history 

Bidwell: I went to Oxford in 1950, not because I had an interest in blood 
coagulation, but because Macfarlane worked on gas gangrene. I worked for seven 
years for the Wellcome Foundation, during the war, on toxins of anaerobic 
bacteria involved in gas gangrene and later on tetanus toxin. Macfarlane wanted 
someone to work on nothing to do with blood coagulation. I got pretty 
browned off to find nobody was interested in what I was doing [they were 
involved in the discovery of factor IX deficiencies] . They realized that I was 
restless, because I didn't want to work all on my own in a corner doing 
something nobody was interested in. So he said to me, 'Well we have got 
nothing to treat these haemophilic patients with, would you like to have a go at 
seeing if you can make something from animal blood?'. So that's how I got 
started in 1952. 

Lee: Which animals did you choose first of all? 

Bidwell: Animals that were slaughtered in a slaughterhouse. I think the first 
thing was the bovine blood. When I got involved, it was done by the 
slaughterhouse men and they were very helpful, very kind. They wanted the very 
best for me. They wanted me to have the animals that had won all the rosettes 
at the shows, but ancient old cows were much better. I went down to the 
slaughterhouse on my Vespa motorbike and I came back with a large glass 
container. I got concerned lest I tipped off my motorbike and tipped blood on 
the floor. 

Lee: How much blood would you be collecting? 

Bidwell: About a gallon. People don't realize that plastics were only just 
coming in. It cost me about the equivalent of a week's wages to buy a plastic 
container to put the blood in so that it wouldn't break on the road to Oxford. 

Lee: What year are we talking about? 

Bidwell: 1952. As I say, I had worked on gas gangrene toxins, Welchii toxins, 
at the Wellcome Foundation and I put that sort of knowledge to use, but I was a 
very pure chemist, who went round bleating, 'What is a cell?' to my colleagues. 
I just had to make use of what was available. There were no refrigerated 
centrifuges. We had to cool them with dry ice and so on. The Blood 
Transfusion Centre was three miles away and they didn't even have a centrifuge 



13 



Haemophilia: Recent history 

to spin their bottles. They used to have to come to us if they wanted to prepare 
blood. People just don't realize the things that weren't there. 

One of our major problems was sterilization, because the properties of the 
factor VIII were such that it wouldn't go through the usual filter media, and 
that's why in the beginning we used to just hopefully give it a high-speed spin 
and put it in a quartz tube and irradiate it; it wasn't really sterile. 

Lee: When did you have the first lot of treatment material that you actually 
were prepared to use? 

Bidwell: It was about 1954 when we started to use it for patients requiring 
tooth extraction, knowing that they were likely to bleed to death if we failed. 
Then in the autumn of 1954, we were called to Norwich for a patient who 
worked in a gun shop and he had got shot by mistake by a customer who was 
trying out a gun! So we went up there and to our horror when we tried the bovine 
factor VIII, the patient had the most awful anaphylactic reactions. We couldn't 
understand this; we hadn't had this sort of reaction before. I am not medical 
myself, so I was chatting away to the technicians while the medical people were 
having talks at a distance and the technicians whispered to me that this patient 
about ten days earlier had been given an Italian preparation which I vaguely 
thought was from bovine material. So I went to Macfarlane and whispered, 
'Can I speak to you?' and I told him about this and of course his face changed 
because he realized the significance - the patient had been sensitized to the 
bovine material. Macfarlane and Biggs had to go back to Oxford, and I and a 
Canadian called Danny Bergsagel, a medical man who was working with them, 
stayed behind and eventually the patient was moved to Oxford in an RAF 
plane. That was the first time I had flown and I was sitting on the floor of this 
plane while a nurse was putting a drip up. I got back to Oxford, the patient 
continued to have reactions to the bovine material and I can remember at the 
end of that week going to Macfarlane and saying, 'There's nothing I can do, can 
I try pig?' and he said, 'Well, go on'. 

The first pig we used was from an animal that was being slaughtered in the 
next village on the Sunday morning. Ross Dike 50 had just joined me and I rang 
him up. That's when we started work and by Wednesday we were treating that 
patient with a course of porcine antihaemophilic globulin. They wouldn't let 
you do that these days. 



50 See Ross Dike's contributions later in this meeting and biographical note 177 below. 

14 



Haemophilia: Recent history 

Lee: No, that's right. One of the things that I hadn't quite understood, and it 
came out when we were speaking with Dr Biggs 51 and again here, is why did 
people push to use animal plasma. I think I am right in saying that Macfarlane 
had made the calculation of how much plasma was needed from human blood 
in the United Kingdom to treat the people with haemophilia and he came up 
with the calculation that it was absolutely impossible; so he therefore said we 
must use animals. Isn't that right? 

Ingram: Yes, that's right. 

Bidwell: Not only that. Again I emphasize this was before the advent of 
plastic, which made all the difference practically. 

Dr Peter Jones: 52 If we can put this into context, this discovery and the large 
scale manufacture, I think later by Maws, 53 of the animal products brought 
treatment particularly to people who had to have major surgery. In the 1960s, 
when I started in haemophilia care, the major operation wasn't reconstructive 
surgery, it was for peptic ulceration with partial gastrectomies, and 
pyloroplasties and vagotomies. There was simply not enough human factor 
VIII in the United Kingdom to treat more than one patient at a time, and so 
we had to turn to the animal products and they were terrific. We used to go for 
pig first, because we thought it was least antigenic and least likely to cause 
thrombocytopenia. The antihaemophilic effect lasted for something like five, 
six, seven, and if you were lucky, eight days, and then we used to change to 
bovine and that would last a similar period. We watched the platelet count but 
never had a clinical problem. Last of all we'd top up with human factor VIII if 
the patient hadn't healed. But that was the position. We used to have to ring 
round to Oxford and to Edinburgh, and to our colleagues in London to get 
enough human factor VIII for one major surgical operation at a time. So the 
animal products were life-saving very early after their introduction. 



op. cit. note 2 above. 

52 Dr Peter Jones FRCP (b. 1937) is Consultant Paediatrician at the Royal Victoria Infirmary, 
Newcastle upon Tyne. He is Director of the Newcastle Haemophilia Centre and an Executive 
Member of the World Federation of Hemophilia. In 1981 he received the Gold Medal 
(Macfarlane Award) of the Haemophilia Society. He has published extensively on 
haemophilia and on AIDS, and is the author of Living with Haemophilia, 4th edition. Oxford: 
Oxford University Press. 

53 It had been arranged that the firm of Maws & Son Ltd should take over the responsibility 
from Bidwell (see note 47 above) for preparing concentrates of animal factor VIII. 

15 



Haemophilia: Recent history 

Ingram: I have here a copy of the surgical course of a patient who had an 
abdomino-perineal excision in October 1959 and who had treatment with ox 
and pig, and human factor VIII. 54 

Lee: Another point that Dr Biggs made was that you [Bidwell] didn't use 
sheep and there was a reason for that. 

Bidwell: There were two reasons. One was that sheep were very woolly, so it 
would have been extremely difficult to collect blood that didn't clot as fast as 
you looked at it. 55 The other is that the relationship between sheep and cows 
was close enough to get a cross reaction. 

Rizza: Dr Bidwell mentioned the horrendous reaction that the man in Norwich 
had, 56 but of course patients nearly always had reactions as the course of therapy 
went on and you had to watch for this and the patients told some lovely stories. 
'Why is it, doctor, I always see stars in front of my eyes when this stuff goes in?' 
and we didn't know why they were seeing stars. In retrospect the suggestion is 
that it may have been platelet clumps going through the retina, because the 
AHG clumped the platelets and the platelets disappeared from the blood as a 
consequence. One ended up sometimes with the patient at risk of bleeding from 
thrombocytopenia, although his haemophilia was better. It was very, very 
interesting. James Matthews 57 and I had many a worrying time with patients 
going on to second courses of treatment and wondering what would happen 
to them. 

Bidwell: Do you remember the terrible cysts that the patients used to have? As 
I say, I am not medical, I was told that according to strict anatomy they 
shouldn't have had those, because there shouldn't have been a track but there 
obviously were and they were frightful. 



54 Copy prepared for the meeting by Ilsley Ingram, taken from Christie T H, Graham-Stewart 
C W, Ingram G I C (1960) Abdomino-perineal resection of the rectum in a haemophiliac. 
Thrombosis et Diathesis Haemorrhagica iv: 224-234, page 229. 

55 The blood on the wool would coagulate very quickly. 

56 This refers to the anaphylactic reaction after treatment with bovine factor VIII of the patient 
with a gun shot wound described earlier by Ethel Bidwell. 

57 Dr James Matthews contributes later in the meeting, see biographical note 110. 



16 



Haemophilia: Recent history 

Rizza: This is the awful thing with haemophilia bleeding of course. It can track 
anywhere. It can destroy soft tissue, it can destroy even bone, because of the 
pressure it can exert in a confined space. 

Your [Bidwell] factor VIII was excellent material and so was the Maws 
material and the Crookes, but the problem we had was getting it into solution. 
It took an hour sometimes or more, shaking bottles, and you had to be careful 
not to shake too hard, because if you got a froth the powder would never 
dissolve, because the factor VIII would sit in clumps on the bubbles and 
wouldn't go into the water. This is one of my recollections, sitting for two or 
three hours shaking. In fact, all of the department used to be involved in this. If 
it was major surgery which was being undertaken, you made up numerous 
bottles and you passed them round to technicians, secretaries, research workers 
and they'd all sit there at tea time drinking their tea and shaking their bottles. 

Dr Brian Colvin: 58 1 want to add a little bit to what Peter [Jones] said about 
peptic ulceration and haemophilia. I still look after a patient who had, I think, 
bovine or porcine factor VIII in 1961 in Oxford and it's important to 
appreciate that people not only got hold of this material, but also referred 
patients to Oxford. For many years, even after my interest began, people were 
being referred to Oxford for treatment and to have their lives saved. It's 
significant perhaps that 40 years later some of these people are still walking the 
planet, who certainly wouldn't be doing so otherwise. 

Perhaps while I have the microphone, I could add a little tiny anecdote to 
Professor Ingram's presentation. Treves's description of the haemophilia scene 
in 1886 in the Lancet® relates to an East End family and concerns a young girl 
called Florence. I never saw her, but her daughter, Edith, broke her hip in a 
strike in 1978 and couldn't be accommodated at The London so she was sent to 
the Royal Free to be operated on. This lady was also probably a true 
haemophiliac and had four sons, all of whom had haemophilia, and the last of 
those sons died last month. So we have a direct link to Treves's description in 
1886. Some years ago our district treasurer asked me how long we had been 
treating haemophilia at the Royal London Hospital and I was able to tell him 
that it was since 1886, which dealt with the argument. 



58 Dr Brian Colvin FRCP FRCPath (b. 1946) is Assistant Warden at St Bartholomew's and The 
Royal London School of Medicine and Dentistry. He has been Consultant Haematologist and 
Haemophilia Centre Director at The Royal London Hospital since 1977 and Director of 
Postgraduate Medical and Dental Education at the Royal Hospitals Trust since 1996. He is a 
Member of the British Society for Haematology and has published many papers on the 
management of haemophilia. 

59 Treves F. (1886) A case of haemophilia, pedigree through five generations. Lancet ii: 
533-534. 



17 



Haemophilia: Recent history 

Lee: Dr Rizza, we just heard then how people were sent to Oxford to have 
treatment. Tell us about the little boy. 

Rizza: Oh, the little boy with Christmas disease. I think he was the first person 
to receive Dr Bidwell's factor IX. I was lucky enough to be working with Dr 
Macfarlane and Dr Biggs in 1959-60 and I used to write home to friends and 
colleagues, telling them episodes about my personal life as well as my working 
life. I told them what I was up to and what was happening at the Centre, what 
was being done in the way of research. It's a thing you daren't do nowadays. 
You keep your notebooks shut; nowadays you must not tell anyone what you are 
doing. Everything was so relaxed in those days, you didn't mind telling people 
what you were doing in the way of research. You didn't expect them to steal 
your ideas or results. I wrote and I said that Dr Bidwell was being successful 
with the factor IX concentrate and that Dr Biggs had made an assay, and that 
soon this concentrate would be available. Promptly, Dr Biggs got a telephone 
call from Dundee where I had come from, asking if she could take on the care 
of a little boy of four, who had had a venepuncture in the antecubital fossa and 
for some reason or other had developed a haematoma at the site of puncture. 1 1 
got huge. It got infected and he ended up with osteomyelitis of the radius and 
he was in a very bad way. He was obviously very frightened, in great pain. He 
was referred to Oxford to be looked after by Professor Trueta, 61 who was 
Professor of Orthopaedic Surgery then, a paediatrician called Dr Victoria 
Smallpeice and Dr Biggs. I remember when we unwrapped his hand, his thumb 
fell off, because his thumb was gangrenous. As soon as he was admitted Trueta 
said, 'This [forearm] must come off, he's very ill, he's infected', and this was 
done. I remember the first dose being given. You, Dr Bidwell, were there 
watching. Dr Bidwell liked to see what the junior doctors got up to with her 
material, so that she knew whether it was the doctor's mishandling of the 
material, rather than the material that caused the problems. The child was taken 
to theatre and given factor IX, and he had to be sedated with rectal pentothal 
every day because he was so frightened. But the operation went very well, the 
factor IX caused no [side] reactions whatsoever, and he healed very well. I know 
that boy well, because when I was up in Scotland last year I went to see him. 
He's now 42 years old, he's an architect, and he tells me that he likes to play 



60 See Rizza C R. (1995) The first patient to receive factor IX concentrate in the UK: a 
recollection. Haemophilia 1: 201—212. 

1 Professor Joseph Trueta FRCS DSc (1897-1977). Following a distinguished career during 
the Spanish Civil War was surgeon in charge of the accident service at the Radcliffe Infirmary 
in Oxford in 1942 and Nuffield Professor of Orthopaedic Surgery at Oxford from 1949 to 
1965. He was succeeded by Professor Robert Duthie (see biographical note 106). See Strubell 
M, Strubell M. (1980) Trueta: Surgeon in war and peace. (Translated memoirs) London: Victor 
Gollancz Ltd. 



Haemophilia: Recent history 

golf. He has only one hand, of course. He did away with his prosthesis very 
early on, because he found the artificial arm more of a nuisance than a benefit, 
and he plays one-handed, right-handed golf. 

Bid well: I remember his ginger hair, bright, bright. I had been putting together 
enough factor IX for some sort of cold operation such as tooth extraction on an 
adult, when you [Rizza] came to me with this story, and, of course, having 
worked with gangrene organisms, it put terror into me. I have never been so 
frightened in my life. 

Rizza: It's sad to say that the man you were saving the factor IX for had 
haemorrhoids and had to have his operation postponed for several months. 

Bidwell: I didn't know what he suffered from. 

Rizza: It's a bit sad, because he was the man who came and gave us blood every 
month for Dr Biggs to develop the factor IX assay, so he thought he was getting 
the assay developed for himself and you were making factor IX for his surgery. 
He, in fact, was a very understanding man. The only point that we haven't 
mentioned is that the development of factor IX went hand in hand with the 
development of good assays, because you didn't know what you were making 
without good assays and you can't do anything without good assays. 

Bidwell: We didn't have access to human plasma for a good long while after 
that and it was decided to see if we could get any factor IX from what they 
were throwing away at Elstree, at the end, when they had taken out albumin 
and gammaglobulin, and factor VIII, which was everything they made. Of 



62 At that time, the large-scale fractionation of plasma was carried out at the Blood Products 
Laboratory of the Lister Institute at Elstree by the ether process of Kekwick and Mackay 
(Kekwick R A, Mackay M E. (1954) The separation of protein fractions from human plasma 
with ether. Medical Research Council Special Report Series No. 286. London: HMSO). This 
yielded, as a by-product, a yellowish, green, greasy residue which was rich in factor IX and it was 
with this that Dr Bidwell and her assistant, Ross Dike, used to extract factor IX. Dr Bidwell 
wrote: 'I am not sure why Kekwick and Mackay did not use Cohn's fractionation method using 
ethyl alcohol, but it is possible a patent covered the latter. It is a great tribute to the skills of the 
early Blood Products Laboratory staff that the place did not explode or burn down. ...I mention 
in the meeting that my earliest starting material for preparing factor IX was the final residue 
from this process. But the first fraction from the process was a concentrate of factor VIII, which 
was supplied from Elstree to clinicians in need. ...Leon Vallet worked at Elstree in getting this 
into production and Dr Snape who worked with me at Oxford, is in charge there now.' Letter to 
Dr Daphne Christie, 

28 March 1999. 



19 



Haemophilia: Recent history 

course, there was a mess with what they threw away, and that was what we used 
for our factor IX, the first type of factor IX. 

Lee: You were just talking about the importance of good assays and you are 
talking now about making the concentrates really rather more formalized. When 
did standardization start, and having standards for assays? When did 
standardization become used either for assays themselves or for assaying the 
material that was being made? When was it realized that that was important? 

Dr Derek Bangham: 63 During the 1960s we [in the Division of Biological 
Standards, National Institute for Medical Research] were constantly on the 
lookout for biological substances which needed standards [reference materials] 
for measurements of macromolecules in human physiology and pathology 
(although not necessarily needed for legal control). Peter Walton, who had done 
a PhD with Ralph Kekwick on factor VIII assays, was working with us, and 
was, perhaps, the first person to prompt us that a standard was needed. He left 
in the early 1960s and the Division was for some years without a haematologist. 
During those years splendid papers by Macfarlane, Rosemary Biggs, Ken 
Denson and others showed the variability of factor VIII concentrations during 
conditions of physical activity, and variability in different people. 5 This was a 
striking example where a standard was needed, for comparisons of assay results. 

In 1966 I went to Oxford and introduced myself to Rosemary Biggs and 
Gwyn Macfarlane. In Rosemary's office I asked her what she used as a standard. 
She turned and pointed to a glass-stoppered sweet jar full of freeze-dried 
bovine factor VIII preparation, and said, 'That's it'. 66 I am a medical, but was 
then innocent of knowledge of blood clotting, and Rosemary, being a rather 
forthright person, was a little taken aback by my proposal for a proper 
standard. But when I'd described the MRC's work on biological standards, and 
the possibility of establishing a WHO international standard, she immediately 



63 Dr Derek Bangham FRCP (b. 1924) was Head of the Division of Biological Standards at the 
NIMR from 1961 to 1972. He was later Head of the Hormones Division of the National 
Institute for Biological Standards and Control (NIBSC), from 1972 to 1987. 

64 Walton P L. (1962) Studies on the proteins of the blood coagulation mechanism in the 
human. PhD thesis, University of London. 

65 op. cit. note. 44 above. See also Denson K W. (1973) Molecular variants of haemophilia B. 
Thrombosis et Diathesis Haemorrhagica 29: 217-219. 

66 Dr Ethel Bidwell wrote: 'I would like to record that my seven years with the Wellcome 
Foundation at Beckenham had ensured that when I had available freeze-dried bovine factor 
VIII, I had at least done accelerated degradation tests showing that the material would be 
sufficiently stable to serve as a standard. It was a great improvement on "pooled normal 
plasma".' Letter to 
Dr Daphne Christie, 28 July 1998. 



20 



Haemophilia: Recent history 

agreed, and from then on was tremendously helpful. It was the start of a very 
good collaboration with her, Ken Denson, Charlie Rizza and Ethel Bidwell in 
setting up several standards for this field of haematology. 

Some citrated plasma was freeze-dried, within four hours of its collection 
at the Edgware Transfusion Centre, in ampoules in the fastidious conditions 
used for biological standards. Ampoules were labelled with code numbers with 
the year in which they were filled and sealed. It was first necessary to 
determine, using accelerated degradation studies, if factor VIII had long-term 
stability. An international collaborative study was organized to compare this 
with a concentrate preparation supplied by Alan Johnson of the New York 
Medical Center, freeze-dried at NIMR in ampoules coded 67/19. Each 
participating laboratory was asked to assay the coded ampoule against their 
own standard, or fresh human blood. 67 The results revealed that what people 
called '1 ml of normal blood' varied from pools of blood, with or without 
various dilutions of citrate. One chap simply used his own blood, day by day. 
It was a very large and complex study, and probably the first international 
study of factor VIII assays involving the world's expert laboratories. It was a 
problem to sort out the huge number 

of results. 

By then we had been joined by a young Yugoslavian haematologist, Dr 
Milica Brozovi_. She helped Joyce Skegg, our statistician, to analyse and 
interpret the results, also helped by Rosemary [Biggs] . The draft report of the 
study was circulated to the participants for agreement. Eventually, in 1970, the 
final report was sent to the Expert Committee on Biological Standardization 
of WHO, which in 1970 formally established the preparation 67/19 as the First 
International Standard for factor VIII. 68 That was a significant step because 
International Units of WHO have legal importance in all countries. Any 
preparation for sale claiming to have factor VIII activity was obliged by law 
to be labelled with those international units. Fortunately, that standard was 
established just in time for the first commercial products that were licensed in 
the UK, and were formally controlled in proper units. 69 



67 As many as 20 laboratories participated in the study. See Bangham D R, Biggs R, BrozovL M, 
Denson KWE, Skegg J L. (1971) A biological standard for the measurement of blood 
coagulation Factor VIII activity. Bulletin of the World Health Organization 45: 337-351. 

68 Dr Derek Bangham wrote: 'When tests for hepatitis became available, the concentrate (the 
International Standard) was found to be contaminated and was promptly replaced with another 
preparation established as the Second International Standard, calibrated in International 
Units against the First International Standard.' Letter to Dr Daphne Christie, 27 July 1998. 

69 See British Pharmacopoeia (1973) Dried human antihaemophilic fraction, 64-65. 
ibid. H. Biological assay of human antihaemophlic fraction, Al 14— All 5. 

21 



Haemophilia: Recent history 

I should add, another preparation of freeze-dried whole plasma, included 
in the study, was established as the British Working Standard, made available 
to Haemophilia Centres all over Britain. 70 It proved to be enormously useful, 
and the twentieth (replacement) working standard is now being distributed. 

Lee: It's very interesting to hear how long ago it was that standardization, 
which is so much part of our life, began. I want to try and change tack a little 
bit, and think about the children who were having treatment. One of the things 
that was said early on was that nobody really thought about what was going to 
happen when these children grew up, because nobody expected them to grow up, 
and it wasn't until they started having treatment that people started organizing 
haemophilia care. We've got some patients in the audience and relatives of 
patients, and we have also got Dr Evans and Dr Jones here, paediatricians. 
Would you like to just try and take us back as far as you can and tell us about 
the children and how treatment came in and the issues? 

Dr David Evans: 71 I thought my brief was actually to continue with a bit of 
the history after Ilsley left off. So I have got a two-part talk really. One is a 
little bit of personal ramblings, which I hope will set ideas off in individuals' 
minds, and perhaps get them remembering things which they may otherwise 
have forgotten, and secondly, more a sort of brief run-down of things that 
happened year by year afterwards. But let's start with the first bit. 

I was an undergraduate at Cambridge in the early 1950s at Downing 
College at a time when Sir Lionel Whitby was Master of Downing. He was, of 
course, the first President of the Haemophilia Society and had an enormous 
fund of information on blood disorders, which he published in his book. 72 1 1 
would be nice for me to be able to say to you that as a result of this marvellous 
experience of meeting Sir Lionel I was inspired with a desire to become a 
haematologist, but it would not be true. All I remember about Sir Lionel was 
that he'd come back from the First World War minus one leg, and with a crate 
of whisky and we all respected him for that. Later in the 1950s, I was a student 



70 Brozovi_ M. (1977) Physiological mechanisms in coagulation and fibrinolysis. British 
Medical Bulletin 33: 231-238. 

71 Dr David Evans FRCPEd (b. 1930) trained in paediatrics at hospitals in Carshalton and 
Lewisham and in pathology at Guy's Hospital, London, before going to Booth Hall and the 
Royal Manchester Children's Hospitals in Manchester where in 1966 he developed a regional 
service for children with blood diseases. In 1972 he set up a Haemophilia Centre at the Royal 
Manchester Children's Hospital. He retired in 1992. 

72 Whitby L E H, Britton C J C (1935) Disorders of the Blood: Diagnosis, pathology, treatment 
and technique. London: J & A Churchill. 



22 



Haemophilia: Recent history 

at St Thomas' where Ilsley Ingram and Roger Hardisty 73 were lecturers in 

clinical pathology. I remember Ilsley Ingram giving me a tutorial, which I 

can't remember much about. But he did talk about von Willebrand's disease 

and that made an impression upon me, but alas it did not inspire me to become 

a 

haematologist either. 

Now, I am going to talk a little bit about blood transfusion at Manchester, 
because of what we probably regard now as blood banking, which of course is 
still terribly important for the early days of haemophilia care. Blood banking 
was really started in the Spanish Civil War by a Basque, Dr Frederick Duran- 
Jorda. He originally worked in the Public Health Department in Barcelona and 
in 1936 he organized a blood transfusion service for the Catalan army during 
the days of the Spanish Civil War. And this was the first time, in 1936, that 
civilian blood donors had been used and their blood was stored to form a 
blood bank, and this was what was original about Dr Jorda's work. 7 In 1937 it 
was extended to the whole of the Spanish Army and Dr Duran-Jorda was 
appointed Director of Blood Transfusion, and he gave lectures in France, 
Switzerland and Czechoslovakia. In 1939 he was invited by the Red Cross to 
come to England. He went to the haematology department of the Postgraduate 
School and lectured to the Royal Society of Medicine. I remind you that other 
Basques left Spain at the same time and that Professor Trueta, 75 who has 
already been mentioned, who was later Professor of Orthopaedic Surgery at 
Oxford, was another one. 

In the same year, 1939, in the expectation of masses of civilian casualties 
from bombing, the National Transfusion Service in the UK was set up. In 1940, 
the following year, Dr Duran-Jorda came to Manchester. In 1950 he was 
appointed Director of Pathology at Booth Hall Children's Hospital and this is 
really why I mention him, because it was the same post that I took over from 
his successor in 1966. In Manchester he would have been in touch at the Royal 



73 Professor Roger Hardisty FRCP FRCPath (1922-1997) qualified at St Thomas' Hospital, 
London, in 1944 concentrating on haematology and particularly the bleeding disorders. In 
1957 he was appointed honorary consultant haematologist to the Hospital for Sick Children, 
Great Ormond Street, London, and over 30 years built up one of the first paediatric 
haematology departments in Britain. He was Professor of Paediatric Haematology at the 
Institute of Child Health, London, from 1969 to 1987, and Professor Emeritus of 
Haematology at the Royal Free Hospital School of Medicine, London, from 1987 to 1997. He 
served as president of several haematological societies and was Editor of the British Journal of 
Haematology. 

7 Dr Frederico Duran-Jorda was Clinical Pathologist to the Public Health Department in 
Barcelona in 1934. In 1936 he organized a blood transfusion service for the Catalan army using 
civilian blood donors. Duran-Jorda F. (1937) El servicio de transfusion de sangre de Barcelona. 
Revista de Sanidad de Guerra 1: 307-321. 

75 See biographical note 61 above. 

23 



Haemophilia: Recent history 

Infirmary with Dr Wilkinson, 76 who was Director of the Department of 
Clinical Research there, which actually developed from a study of gastric 
function into one in pernicious anaemia and is now a department of 
haematology. Dr Wilkinson organized the blood transfusion services in the 
north-west. He is now over 100 years old 77 and is a vice-president of the 
Haemophilia Society. It is fair to say that Dr Duran-Jorda had an original 
mind, but I regret to have to tell you that he published one of his original ideas 
in Nature in 1947 and it was that red blood cells originate from the granules of 
eosinophils. 78 

I want to talk a little bit about my early contacts with the use of factor 
VIII concentrate, because in 1957, which was when I qualified, Kekwick and 
Wolf reported on the use of a factor VIII concentrate in the treatment of six 
cases of haemophilia. 79 Two years later I was a Registrar at Lewisham, and 
Peter Wolf was still pouring these dreadful soups and thick creamy stuff into 
individuals with haemophilia. I was very concerned that they were going to go 
into cardiac failure because he was putting in this stuff so fast, but fortunately 
they were predominantly young men with good cardiovascular reserves and I 
think that apart from a tachycardia and a shortness of breath, we didn't have any 
complications. Dr Holman was the haematologist at Lewisham in those days, 
and I think it is quite appropriate that we remember that haematologists as we 
know them now did not exist. The patients were all under the care of general 
physicians and a haematologist was a specialist in the laboratory who got 
interested in aspects of blood and blood management. There were very, very 
few clinical haematologists. 

I went to Manchester in 1965 and that was the year in which Judith Pool 
described cryoprecipitate. 81 We didn't get cryoprecipitate in Manchester until 
much, much later. We used fresh, so-called 'snap-frozen' plasma. Dr Stratton 
was the Director of the Blood Transfusion Service in Manchester at the time 
and he was a very autocratic individual. He really believed that all people 
wanted from a blood transfusion service was what he called 'the pint', and he 
would hold up a bottle of blood, because the blood came in bottles with a 



76 Dr John Wilkinson (1897-1998) was Director of the Department of Haematology at 
Manchester Royal Infirmary from 1947 to 1962 and set up the first blood transfusion service in 
Manchester. He was cofounder of the British Society of Haematology, President of the 
European Haematology Society and a Life Councillor of the International Haematology 
Society. 

77 Dr Wilkinson died shortly after the meeting, on 13 August 1998. See biographical note 76. 

78 Duran-Jorda F. (1947) Secretion of red blood corpuscles. Nature 159: 293-294. 

79 See Kekwick R A, Wolf P. (1957) op. cit. note 22 above. 

80 At that time the concentrates came in bottles as an opaque thick creamy juice. 

81 See note 24 above. 



24 



Haemophilia: Recent history 

waist in those days, and he'd say, 'Look at that, doc, that's the pint, that's what 
you want'. And all the doctors in the Transfusion Service were called 'Doc' by 
the workers, and by Fred [Stratton] himself. He provided a very good service, 
but he never thought it was a business of his department to provide blood 
fractions. 

So very shortly after arriving in Manchester when I had a baby with a 
cerebral haemorrhage, I couldn't get anything other than plasma to treat him 
with. In fact I managed to get some cryoprecipitate which was being made for 
the first time in Manchester by Dr Watson-Williams at Manchester Royal 
Infirmary. It seemed to work, the child recovered, but subsequently died, but it 
inspired us to buy a large vacuum flask and we made our own cryoprecipitate. 
But whereas in London there had been no difficulty in obtaining blood donors, 
because there was a Red Cross panel, you phoned up the Red Cross and they sent 
somebody along, any hour of the day or night, Manchester had never developed 
that concept. There were special donors, but they all had individual and 
particular blood groups and they were called up when a funny blood group was 
needed, not when you wanted blood in a hurry. So we had extreme difficulty in 
getting donors to provide us with blood from which you could make the 
cryoprecipitates. I remember we had to buy the blood bags and we got them 
from Tuta (Australia), because they were cheaper than from Baxter, 82 and that 
caused problems because the hospital hadn't had to buy blood bags before and 
they wouldn't authorize the purchase because they thought that was the job of the 
Blood Transfusion Service and, of course, as I told you, the Blood Transfusion 
Service wouldn't do it. Eventually we got cryoprecipitate from the Blood 
Transfusion Service and continued to use it for a very long time, because there 
were no funds to buy imported concentrate. 

Actually, this proved to be a benefit, because as a result only a rather small 
percentage of our boys developed human immunodeficiency virus (HIV), 
because they had been treated with British cryoprecipitate, rather than imported 
[contaminated] American concentrate. When cryoprecipitate did become 
available Dr Stratton wouldn't provide it to outlying hospitals, and he insisted 
that the patients be referred either to me at Manchester if they were children, or 
adults to the MRI (Manchester Royal Infirmary) . That led to our setting up our 
own Centre in the children's hospital in 1972. That's a little bit about my 
personal involvement. 

What I want to do now is to run through a sort of annual summary of the 
way things developed. In the 1970s we were starting to use much more freeze- 
dried concentrate in the UK and gradually amounts were beginning to become 



82 Manufacturers Tuta (Australia) and Baxter (UK) supplied plastic blood bags to the English 
National Blood Authority and Scottish National Blood Transfusion Service. 

25 



Haemophilia: Recent history 

available. The Bethesda assay for inhibitors was developed in 1975 which 
helped standardize assays round the world. 83 Lots of the methods, I think, were 
very good, but they weren't used everywhere and, I think, standardization, as we 
have just mentioned, was very important. I think the Bethesda assay was helpful 
in that. 

In 1976 the Department of Health published HC-76/4, recommending 
three-tier arrangements for haemophilia care. By that time a large number of 
hospital laboratories were able to do factor VIII assays and a lot of 
haematologists were being appointed because the College of Pathologists was 
well under way by then and the concept of having a small centre came into 
being. I think it was a mistake, because the Haemophilia Society and those 
people who deal with a large number of patients feel that it is better to 
concentrate patients in a larger unit where there can be a depth of expertise 
rather than in a small unit. The problem with the small unit has always been you 
have an enthusiastic haematologist leading it, but when he goes on holiday there 
is nobody to take his place and the surgeons don't know anything about it and 
the system falls down. That's just a personal view. 

In 1978 fetal blood sampling in utero [in the second trimester] enabled us 
to check the sex and the factor VIII or IX level, and to offer termination of 
pregnancy to those women who wanted it. 85 My experience was that only a 
minority of women wanted termination. 

In 1982 the gene for factor IX was cloned. Factor IX was cloned before 
factor VIII because it is a smaller molecule, not so complicated and was easier 
to work on. In the same year, eight individuals with haemophilia and acquired 



83 A meeting was held in November 1974, sponsored by the Division of Blood Diseases and 
Resources, National Heart and Lung Institute, USA, to address the problem of non-uniform 
inhibitor measurement. It was agreed to standardize inhibitor measurements and to describe a 
'Bethesda unit' to be used in the measurement of inhibitors arising in haemophiliacs. 
See Kasper C K, Aledort M, Aronson D, Counts R B, Edson J R, Fratantoni J C, Green D, 
Hampton J, Hilgartner M, Lazerson J, Levine P, McMillan C, Pool J G, Shapiro S, Shulman 
N R, van Eys J. (1975) A more uniform measurement of factor VIII inhibitors. Thrombosis et 
Diathesis Haemorrhagica 34: 869-872. 

84 Department of Health. (1976) Arrangements for the Care of Persons Suffering from 
Haemophilia and Related Conditions. HC-76/4. London: HMSO. The three-tier system 
comprised Reference Centres (which later became Regional Centres), Haemophilia Centres 
and Associate Haemophilia Centres. 

85 Rodeck C H, Campbell S. (1978) Sampling pure fetal blood by fetoscopy: in second 
trimester of pregnancy. British Medical Journal ii: 728-730. Mibashan R S, Rodeck C H, 
Thumpston J K, Edwards RJ, Singer J D, White J M, Campbell S. (1979) Plasma assay of fetal 
factors VIIIc and IX for prenatal diagnosis of haemophilia. Lancet i: 1309—1311. 

86 Choo K H, Gould K G, Rees D J H, Brownlee G G. (1982) Molecular cloning of the gene 
for human anti-haemophilic factor IX. Nature 299: 178-180. 



26 



Haemophilia: Recent history 

immunodeficiency syndrome (AIDS) were reported in the United States. 87 In 

1983 parvovirus was found to be spread by concentrates. 88 Factor Vila - that's 
plasma-derived factor Vila - was first used in 1983 to treat inhibitor patients 
and the first two British cases of haemophilia and AIDS were reported. 89 In 

1984 the gene for factor VIII was cloned. I think the initial hope was that 
because we could clone factor VIII, we would be able to make an instant 
diagnosis, but because it's such a large and complicated molecule there were an 
enormous number of defects, and hopes that antenatal diagnosis based on 
genetic testing with both factor VIII and factor IX would be easy, proved to be 
quite the reverse. 

In 1985 tests for HIV were introduced to the Blood Transfusion Service 
and in fact tests for HIV became generally available. We were all asked by the 
parents of the children we were looking after, 'Please test our children' and 
that's what we did. But we read the message wrongly. What they were asking us, 
without saying so, was, 'Please find my boy is negative'. In those days when the 
first test came out, the concept of counselling was really not very well 
understood, and certainly we didn't understand it. We told the parents the 
results and then an enormous flood of anxieties and queries came in and people 
came and talked to us. It was a topic of enormous interest to patients at the 
time. The north-west group of the Haemophilia Society had its annual general 
meeting in Manchester. Peter Jones was invited to come and give a talk about 
HIV, and 400 people came to 

hear him. We had to move into a larger lecture theatre. It was a larger number 
than any attendance at a general meeting of the whole Haemophilia Society 
in London. 

But we did have a lot of problems with HIV, not so much dealing with the 
individual cases of treatment, but in dealing with children through their parents. 
When the test was first introduced, a large number of our boys were quite small, 
but as time went by, little boys of 12 became big boys of 16 or 17 and it 
became time for them to know. In a children's hospital, it is very difficult to 
inquire into the sexual habits of your patients. It is just not in the ethos of a 
children's hospital, and we thought that all these boys should know their HIV 
status. Whether or not they would actually modify their behaviour we very much 
doubted, although we did have condoms available in the Haemophilia Centre. I 



87 Evatt B L, Gomperts E D, McDougal J S, Ramsey R B. (1985) Co-incidental appearance of 
LAV/HTLV-III antibodies in haemophiliacs and the onset of the AIDS epidemic. New 
England Journal of Medicine 312: 483-486. 

88 Mortimer P P, Luban N L C, Kelleher J F, Cohen B J. (1983) Transmission of serum 
parvovirus-like virus by clotting factor concentrates. Lancet u: A&2-A&A. 

89 Jones P. (1983) Acquired immunodeficiency syndrome, hepatitis and haemophilia. British 
Medical Journal 2%7: 1737-1738. 



27 



Haemophilia: Recent history 

should not think that many children's hospitals in this country would have 
condoms available. It proved very difficult to get them to talk and it proved 
impossible to persuade their parents to tell them. Eventually we came to an 
agreement that if the boys asked, we would tell them. Various ways and means 
were found to raise the topic so the boys actually asked us, so they could be 
told. One father came to my office at eight o'clock in the morning and he said, 
'I hear what you are planning to do. On no account should my son be told, it 
will destroy him'. Eventually the boy found out and said he was grateful to be 
told because it was all hushed up so much at home that he thought something 
much more serious must be afoot. You will all remember how dreadful it was 
at the time with the television advertisements showing rolling waves and 
talking about HIV and safe sex, and so forth. 90 When this happened in a 
haemophilia household the television was turned off. People just could not bear 
up to it, they had to turn their heads away. So our problem with HIV was really 
as much dealing with the parents as actually treating the boys who were positive. 

Back to the sort of sequence of events. In 1988 recombinant factor Vila was 
introduced for treating inhibitor patients 91 and that year was also the first time 
that the recombinant factor VIII concentrate was used. 1989 was another 
milestone year - hepatitis C was identified. 92 In 1990 the Macfarlane Trust 
was set up to distribute funds to people with haemophilia and HIV. In 1992 a 
setback came when people realized that solvent-detergent-treated concentrates 
could spread virus infections in the form of hepatitis A. 93 By 1993 the Health 
Services Guidelines (93/30) came with the recommendation of a two-tier 
system of Haemophilia Centres. They recommended what services should be 
available, but made no recommendations whatsoever about what physical 
facilities, what buildings, clinics and so forth should be made available, and 
that I think has led to certain problems for some Centres. In 1994 the 



90 In the 1980s bold television advertisements were used for public education on AIDS. See 
Berridge V. (1996) AIDS in the UK. The Making of Policy, 1981-1994. New York: Oxford 
University Press, 113—114. 

91 Hedner U, Glazer S, Pingel K, Alberts K A Blomback M, Schulman S, Johnsson H. (1988) 
Successful use of recombinant factor Vila in a patient with severe haemophilia A during 
synovectomy. Lancetii: 1193. 

92 Choo QL, Kuo G, Werner A J, Overby L R, Bradley D W, Houghton M. (1989) Isolation of a 
cDNA clone from a blood-borne non-A non-B viral hepatitis genome. Science 244: 359—362. 

93 Mannucci P M, Gdovin S, Gringeri A Colombo M, Mele A, Schinaia N, Ciavarella N, 
Emerson S U, Purcell R H. (1994) Transmission of hepatitis A to patients with hemophilia by 
factor VIII concentrates treated with organic solvent and detergent to inactivate viruses. Annals 
of Internal Medicine 120: 1-7. 

9 This replaced the three-tier system HC-76/4, see note 84 above. Department of Health. 
(1993) The Provision of Haemophilia Treatment and Care. Health Services Guidelines HSG 
(93)30. London: HMSO. The two-tier system comprised Comprehensive Care Centres and 
Haemophilic Centres. 



28 



Haemophilia: Recent history 

UKHCDO [United Kingdom Haemophilia Centre Directors Organization] 95 
was set up and registered as a charity and by 1997 things were working very 
nicely until Creutzfeldt-Jakob disease (CJD) raised its head and produced a 
lot of anxiety, not so much for haemophilia but for blood transfusion services in 
general. 

Other things which have come up, related to haemophilia and which I have 
not actually dated, are the use of a continuous infusion of a concentrate/ What 
has been extremely important, but often ignored, is the introduction of small 
needles and butterfly needles and later, in-dwelling venous catheters and Port-a- 
Caths for the management of haemophilia care; 97 and another topic which is 
covered very little in the UK is radiosynovectomy 98 which has been perhaps 
more popular in parts of the world where concentrate has been less readily 
available. 

Dr Helen Dodsworth: 99 1 used to work at St Mary's Hospital, London, after 
working in Manchester, alongside Dr David Evans. May I say briefly 
something about the availability of factor VIII concentrate? Although the 
manufacturing process was discovered in the early 1950s, 101 there was never 
adequate provision for manufacture of factor VIII concentrate in this country 



95 See also Rizza's contribution on page 53 below. 

96 Giving concentrate by continuous infusion was first reported in 1970. See McMillan C W, 
Webster WP, Roberts H R, Blythe WB. (1970) Continuous infusion of factor VIII in classic 
haemophilia. British Journal of Haematology 18: 659-667. Bona R D, Weinstein R A, Weisman 
S J, Bartolomeo A, Rickles F R. (1989) The use of continuous infusion of factor concentrates in 
the treatment of hemophilia. American Journal of Hematology 32: 8-13. 

97 Dr Jones remembers how, when he worked as a junior doctor with Dr William Walker (later 
first Professor of Haematology in the University of Newcastle upon Tyne), he had to make the 
devices that later emerged as butterfly needles and intracaths. Hypodermic needles were cut off 
their hubs with pliers and either threaded by, or attached to, thin plastic tubing. The results 
were used in the treatment of babies with haemolytic disease of the newborn. Letter to Dr 
Daphne Christie, 1 July 1999. 

18 See Pietrogrande V, Dioguaardi N, Mannucci P M. (1972) Short-term evaluation of 
synovectomy in haemophilia. British Medical Journal!: 378-381. Kay L, Stainsby D, Buzzard B, 
Fearns M, Hamilton P J, Owen P, Jones P. (1981) The role of synovectomy in the management 
of recurrent haemarthroses in haemophilia. British Journal of Haematology 49: 53-60. 

99 Dr Helen Dodsworth FRCP FRCPath (b. 1938) was Honorary Consultant Physician at St 
Mary's Hospital Medical School, London, from 1970 to 1993 and Founder Member of the 
British Blood Transfusion Society in 1983. She was a Member of the British Society of 
Haematology from 1972 to 1993 and has published several papers on blood transfusion-related 
topics including: Dodsworth H. (1996) Blood transfusion services in the UK. Journal of the 
Royal College of Physicians of London 30: 457-464. Gunson H H, Dodsworth H. (1996) 50 years 
of blood transfusion. Transfusion Medicine 6: 1-88. 

100 See biographical note 71 above. 

101 op. cit. note 23 above. 

29 



Haemophilia: Recent history 

until the early 1970s. 102 In 1972-73, a unit dedicated to the production of 
plasma fractions and managed by the MRC was built on the Elstree site. 103 At 
about this time the anticoagulant into which donor blood is taken was changed 
from acid-citrate-dextrose (ACD) to citrate-phosphate-dextrose with adenine 
(CPD-Ad). ACD has a pH of 5.0 rising to 6.8 after the addition of blood. 
Factor VIII, however, is stable over only the narrow pH range of 7.1-7.2, the 
final pH achieved when blood is added to CPD. Although the introduction of 
CPD-Ad increased the potential for factor VIII production, facilities at 
Elstree were inadequate to produce the quantities which were needed. 

In 1 976 Pat Mollison, for whom I was working at the time, asked me to 
represent him on a committee convened to advise the Department of Health on 
how much factor VIII concentrate and albumen were needed to treat patients in 
the UK. Our spokesman, Dr Tovey, 105 the Director of the Bristol Transfusion 
Centre, had been through a similar exercise for the World Health Organization 
in Geneva. He persuaded us that if we wanted to treat our patients adequately, i t 
would be necessary to fractionate at least 80 per cent of the blood that was 
donated. At this point the Government decided that money was available for 
neither extending the fractionation unit at Elstree nor for equipping the 
transfusion centres to separate yet more plasma from donor units. So this is 
really why we found ourselves buying large quantities of factor VIII concentrate 
from America, and why we infected so many of our patients with HIV. 

Professor Robert Duthie: 106 I was interested in what Dr Evans has said 
about a small unit in a big department. This tends to lead to difficulty in the 
admission of haemophilic patients, and the follow-up organization, as well as 
educating members of the team. Oxford has been unique, in that haemophilia 



102 Anon. (1974) Factor VIII concentrates made in the United Kingdom and treatment of 
haemophilia based on studies made during 1969-72. Report of the Medical Research Council's 
Blood Transfusion Research Committee Working Party on the cryoprecipitate method of 
preparing AHF concentrates. British Journal of Haematology 27 ': 391-405. 

103 op. cit. note 62 above. 

104 Professor Patrick Mollison FRCP FRCOG FRCPath FRS (b. 1914) has been Honorary 
Consulting Immunohaematologist to the South East Regional Service since 1983 and Professor 
Emeritus of Haematology, St Mary's Hospital, London, since 1979. He was Director of the 
MRC Experimental Haematology Unit from 1960 to 1979 and Consultant Haematologist at 
St Mary's Hospital, London, from 1960 to 1979. 

105 Dr Geoffrey Tovey FRCP FRCPath (b. 1916) was Director of the South West Regional 
Blood Transfusion Centre from 1946 to 1978 and President of the International Society of 
Blood Transfusion from 1973 to 1976. He was also Consultant Adviser on Blood Transfusion 
at the Department of Health and Social Security from 1979 to 1981. 

106 Professor Robert Duthie CBE FRCS (b. 1925) was Professor and Orthopaedic Surgeon in 
charge of orthopaedic surgery at the University of Rochester Medical Center, Rochester, New 
York, from 1958 to 1966 and Nuffield Professor of Orthopaedic Surgery, University of 
Oxford, and Nuffield Orthopaedic Centre, from 1966 to 1992, Professor Emeritus since 1992. 



30 



Haemophilia: Recent history 

has always been a separate and large department run as a multidisciplinary 
specialty with good staffing in all disciplines, e.g. nurses, doctors, teachers, 
social workers, physiotherapists, etc. and in the supply of orthopaedic beds for 
those haemophiliacs who have musculo-skeletal bleeds, i.e. 85 per cent. I am 
afraid that this may be an old argument but I think that one of the real advances 
made in Oxford was when the Haemophilic Unit consisted of a full team, 
including your sic 'uneducated surgeons' who, with further training can provide a 
learning experience for others. HIV, with its biological problems, introduced 
an ethical one. Professional people were very much concerned about their degree 
of risk and the infectivity of materials from operations. Indeed, in America, 
surgeons used this as a new indication for doing or not doing surgery. Because of 
the additional risk of HIV, pathologists were refusing to do post mortems or 
handle operative material. This ended a very fruitful number of years in which a 
much more accurate definition of the local pathology of haemophilia had been 
worked out. People were scared of using local tissues for analysis, e.g. by 
spectroscopy, and so this form of research ceased. So, HIV had a much greater 
impact than just on immunology or infectivity. For example, although HIV 
was one of the indications for using synoviorthrosis, this was limited because of 
the discovery of chromosomal breakages identified in the patients undergoing 
radiosynovectomy. Obviously, in many places in the world where factor VIII 
is scarce this is a preferred method, but in England we continue to undertake 
surgical synovectomy because of the availability of factor VIII and because of 
the knowledge of outcome. 107 

One of the reasons why I returned to England from the United States was 
the privilege of being able to work in the Oxford Haemophilic Unit, after 
having set up a small Orthopaedic Centre in the University of Rochester, New 
York. Oxford has provided a large grouping of patients of all ages without the 
artificial division of being a child one day and an adult the next. Obviously 
haemophilic patients were living much longer, well into adulthood and old age, 
with the development of degenerative processes requiring to be operated upon. 
This was common until HIV appeared. Suddenly we lost between one-third 
and two-thirds of our haemophilic patient population. Indeed, there are now 



107 Professor Robert Duthie wrote: 'We discovered that only 10 per cent of haemophilic 
patients with chronic synovitis required surgery; the remainder responding to conservative 
management by factor replacement, compression bandaging and subsequent careful 
physiotherapy. The complications of ongoing haemorrhaging into the musculo-skeletal tissues 
were controlled and dealt with in our Centre by conservative treatment. This then allowed 
further development in elective orthopaedic surgery: management of severely damaged joints by 
replacement; the management of progressive haemophilic cyst formation, by internal fixation 
systems in order to prevent pathological fractures, with the increased mortality rates; the 
prevention of fixed flexion contractures, caused by muscle haemorrhages, by dynamic splinting, 
etc. All giving marked improvement in the musculo-skeletal tissues of mobility, reduction in 
deformities and improved function.' Letter to Dr Daphne Christie, 24 July 1998. 

31 



Haemophilia: Recent history 

two main areas in the epidemiology of haemophilia, pre- and post-HIV 
infection. This is of particular importance when it became necessary to examine 
our surgical and conservative treatment modalities. A lot of epidemiological 
studies have yet to be carried out on the effect of surgery upon the immunology 
status of HIV patients. 

Lee: Can you talk a little about when you first started doing elective surgery in 
these patients and what it really involved for you as a surgeon, and the team 
work involved? Can you remember the first elective surgery that you did on 
these patients? 

Duthie: Very, very clearly. Charles [Rizza] is smiling as well, because, of 
course, the usual discussion which we carried out was about the availability of 
factor material, the actual quantity required for the operation, for healing to 
take place, and whether or not there was enough. The golden rule was that there 
had to be enough on the shelves before we embarked upon any surgery. Then one 
changed the surgical attack because of the availability of sufficient factors, and 
also because we began to understand the pathology and subsequent healing of 
haemophilic tissues which were, and are, different. However, what we had learnt 
from poliomyelitis patients all added to the knowledge required to 
rehabilitate a haemophiliac after surgery. 108 The simpler the operative 
technique the better, because the healing of the tissues would be less demanding 
upon factor supply. The development of the factor VIII antibodies was very 
critical because with antibodies elective surgery was contraindicated. Actual 
operating techniques were modified by use of electrocautery, compression post- 
operatively, and fibrin injection into haemophilic cysts and their walls. We 
devised a type of sterile air operative enclosure in Oxford in order to reduce, 
to the lowest level possible, surgical infection rates in the haemophilic patient, 
with great success. It became even more important when we were operating on 
HIV patients (up to two a week), in being able to isolate and reduce the 
surgical team with more control 



108 Professor Robert Duthie wrote: 'This aspect of rehabilitation is highly specialized and 
carried out by many committed individuals, e.g., nurses, physio-occupational therapists and 
social workers. The aim is to restore the patient back to school or to work, by overcoming 
muscle weakness, stiffness and joint immobility, negative attitudes towards educational, daily 
living and recreational activities. Working under haemostatic control by factor replacement, 
dynamic splintage, orthotics, compression air splints, new skills of proprioceptive 
neuromuscular facilitation (TENS - transcutaneous electrical nerve stimulation) are now 
available to improve the results of surgery and the treatments of bleeds.' Letter to Dr Daphne 
Christie, 22 March 1999. 



32 



Haemophilia: Recent history 

in the numbers around the patient, handling the patient, materials 
and instruments. 109 

Lee: Dr Matthews, could I try and encourage you to talk a bit about the 
beginnings of treatment for patients, regular home treatment for patients, and 
maybe we can draw out of you a bit about needles and the changes that came in 
with decent needles and things like that. 

Dr James Matthews: 110 I came to Oxford in 1961 and before that time 
transfusion equipment was rather unreliable. The rubber and glass drip sets 
sometimes came apart in the middle of a transfusion and created havoc. 
Needles and syringes in 1961 were still of a type that had been used for many 
decades. Needles were all steel, sterilized by autoclaving after use and 
resharpened in a machine similar to that used for sharpening gramophone 
needles. They were sometimes blunt or even had a hooked point! They were 
packed for use in glass tubes and the size was identified by a twist of coloured 
cellophane which closed off the end of the tube. The syringes were of glass and 
sometimes stuck whilst drawing blood or giving an injection, usually at the 
worst possible time, particularly if you were dealing with a child. For some 
time after I came 

syringes were autoclaved in aluminium canisters. Blood sample tubes for 
coagulation studies were prepared in the laboratory, as were pipettes and many 
of the test reagents. 

When dealing with bleeding patients in the early days, one of the main 
problems was shortage of treatment material. The material most commonly 
used was fresh-frozen plasma. This was a material which was relatively easy to 
obtain and became more plentiful as the blood transfusion organizers allocated 
more for the treatment of haemophilia. We were very fortunate in Oxford in 
having Dr Jean Grant as Director of the Blood Transfusion Service. She was one 
of many consultants who cooperated closely with the Haemophilia Centre. 1 1 
was a time when the clinicians at the Haemophilia Centre had access to the key 
of the Blood Transfusion Centre and could obtain plasma out of hours without 
delay. Plasma was used for the treatment of many of the common bleeding 



109 Professor Robert Duthie wrote: 'Because of having sufficient numbers going through our 
specialized operating facilities the discipline and the efficiency of the team were readily 
worked out, and indeed there was no further need to use HIV as an excuse or as another indicator 
of whether surgery was indicated.' Letter to Dr Daphne Christie, 24 July 1998. 

110 Dr James Matthews (b. 1930) was Clinical Research Fellow at the MRC Blood Coagulation 
Research Unit, Churchill Hospital, Oxford, from 1962 to 1965, with a special interest in the 
clinical management of haemophilia and other bleeding disorders. He remained at the Oxford 
Haemophilia Centre as an Associate Specialist until his retirement in 1991. 

33 



Haemophilia: Recent history 

episodes which responded to the limited factor level achievable with the 
material. Allergic reactions were not uncommon and the volume of infusion 
required was a disadvantage particularly in children who might be upset and 
restless at the time. A few years passed, and more of the human and animal 
factor VIII concentrates became available and treatment became easier in 
terms of the volumes used and the factor levels which could be achieved. Home 
treatment was not used for some time as the materials were in short supply and 
those which were available were not really suitable for using at home. 

Lee: Was it right to think that cryoprecipitate was a thing that really pushed 
home treatment? 

Matthews: It did make a big difference, because it was easily made. It still 
wasn't the ideal material because it was a liquid plasma product stored in the 
frozen state but many Centres found it a very useful material for home 
treatment. 

Lee: In our own Centre, Katharine Dormandy really made a major 
contribution. I think I am right in saying that she made cryoprecipitate in the 
old hospital at Lawn Road in the labs there, 112 and that the patients were 
actually started on home treatment with cryoprecipitate. In fact, if you go back 
and look through the notes of some of our older patients, the social work 
contribution was to raise the money to buy the deep freezers enabling them to 
have it at home. 

Rizza: I think Katharine Dormandy was one of the few to start using cryo 
[precipitate] for home therapy. I remember having a discussion with her about 
the problems of fridges without alarms on them, because if the patients were 
going to keep cryoprecipitate at home, deep frozen, then they had to know if 
the fridge had gone off, when they went away for the weekend. They had to have 
an alarm system fitted and those were very expensive at that time. 



111 Dr Katharine Dormandy FRCP (1926-1978) qualified at the Royal Free Hospital School 
of Medicine in 1951 and was appointed Senior Lecturer in Haematology in 1964 and Reader 
in Haematology in 1970. She developed the Haemophilia Centre at the Royal Free Hospital, 
London, raising money personally and campaigning tirelessly for better treatment for people 
with haemophilia and better educational opportunities for haemophilic boys. She was a 
pioneer of home treatment. In 1977 she was awarded the first gold medal of the Haemophilia 
Society. The Centre named in her honour was opened in 1978. See also notes 114, 125, 170 and 
171 below. 

112 See note 171 below. 

34 



Haemophilia: Recent history 

Lee: There's a sort of interesting twist in that tale, which Ted [Tuddenham] 
might throw a bit of light on. In our Centre we were a bit slow to use large full 
clotting factor concentrate, because it wasn't really until you and Peter Kernoff 
came that people were started on this treatment, because Katharine had been so 
taken up with the cryoprecipitate. Is that fair? 

Matthews: I think it is probably fair to say that we used the freeze-dried 
pooled plasma concentrate in preference, because it was available to us and 
seemed a suitable material for home treatment. 

Professor Edward (Ted) Tuddenham: 113 Katharine had a wonderful 
relationship with her patients. It was maternal in some ways, because she knew 
them all very well and their social circumstances, she put a very great deal of 
effort into ensuring that they would have the best possible circumstances for 
home treatment. She was a pioneer in that area and obtained, as you 
mentioned, money for them to have freezers in their own homes in which they 
kept cryoprecipitate. I would say that, to be fair to Katharine, it was difficult, 
as other speakers have mentioned, to obtain adequate supplies of higher-purity 
concentrates other than for surgery, and the Centre's treatment relied very much 
on cryoprecipitate produced through local blood transfusion centres. Things 
changed, of course, when Peter Kernoff and I came in after Katharine tragically 
died, and the concentrates were brought in progressively through battles against 
the controllers of the finances. Although to do them justice, they did 
progressively increase the fraction of local capital that was being expended on 
imported concentrates until they reached towards the dizzying heights of today. 
So it was a transitional phase. Katharine was a pioneer and it undoubtedly 
changed the lives of our patients at that time to have their own freezers filled 
with locally produced cryoprecipitate. 



113 Professor Edward Tuddenham FRCP FRCPath (b. 1944) was Co-director of the 
Haemophilia Centre, The Royal Free Hospital, London, from 1978 to 1986, and Director of 
the MRC Haemostasis Research Group at Northwick Park Clinical Research Centre from 
1987 to 1994. He has been Director of the Haemostasis Research Group, Clinical Sciences 
Centre, Imperial College Medical School, London, since 1994 and Honorary Consultant 
Haematologist at the Hammersmith Hospital, London, since 1994. He is a Member of the 
World Federation of Hemophilia, the International Society on Thrombosis and Hemostasis, 
and the British Society of Hemostasis and Thrombosis. 

114 See for example Le Quesne B, Britten M I, Maragaki C, Dormandy K M. (1974) 
Home treatment for patients with haemophilia. Lancet ii: 507-509. Ingram G I, Dykes S R, 
Creese A L, Mellor P, Swan A V, Kaufert J K, Rizza C R, Spooner R J, Biggs R (1979) Home 
treatment in haemophilia: clinical, social and economic advantages. Clinical and Laboratory 
Haematology 1: 13-27. 

35 



Haemophilia: Recent history 

JoneS: Yes, just to go back to cryo [precipitate]. Judy Pool discovered cryo 
[precipitate] m - it was another case of serendipity really. She was looking at 
the various bits of concentrate and she was going to throw away the gunge. I 
think it was Shannon who decided to test the gunge for factor VIII and 
discovered all the factor VIII was in the gunge and that was cryoprecipitate. 
Judy came to Newcastle in the mid-1960s and the day after her visit the blood 
transfusion service made the first pack of cryoprecipitate. The introduction of 
cryo [precipitate] revolutionized the care of children, because previously we had 
to give so much fresh-frozen plasma, particularly to patients with factor IX 
deficiency because of their poor response, that they used to go into heart failure. 
So they were all on digitalis and diuretics and they lay in bed on the dreaded 
drip, and it was hardly surprising that they never wanted to come to hospital 
again. But if they bled sufficiently they had to! My first patient was in hospital 
27 times before his fifth birthday and, worse than that, he saw 17 different 
doctors. Nobody was interested in haemophilia. Haemophilia was 'a bloody 
nuisance' and kids with haemophilia were 'bloody nuisances'. Only one in 16 
000 of the population has severe transfusion-dependent haemophilia, and so it's 
easy to see where the resistance came from. There was great resistance, 
particularly from the Blood Transfusion Service of this country and certain of 
its directors, to treating haemophilia at all, except as a hospital disease. There 
was great resistance to home therapy. There were letters in the medical press 
and the lay press, suggesting that people with haemophilia were not capable 
of treating themselves, that their parents should not take responsibility for them 
at home, that it was dangerous and unethical and immoral to put treatment into 
their hands. In two European countries, Italy and, I think, Spain at the time, it 
was illegal for patients to inject themselves with any medication, including 
factor VIII or factor IX. So there was an enormous inertia to overcome. The 
other feature of medicine in those days that we tend to forget was its 
paternalistic nature; the doctor always knew best, nurses really didn't come into 
it, and it was thought that it was not right to educate patients. It sounds terrible 



See note 24 above 

116 The difficulties in implementing home therapy because of the shortage of concentrates are 
reported in the Lancet in 1974. See for example Biggs R. (1974) Supply of blood-clotting 
factor VIII for treatment of haemophilia. Lancet i: 1339. Lay articles about the shortage and the 
difficulties for both patients and staff, including comments opposing home therapy, were 
published in the Yorkshire Post in 1975 and 1978. Dr Jones was Chairman of the UK Home 
Therapy Working Party at the time, and reported the situation in the UK in the British Medical 
Journal. See Jones P, Fearns M, Forbes C, Stuart J. (1978) Haemophilia A home therapy in the 
United Kingdom 1975-1976. British Medical Journal i: 1447-1450. Mr Clifford Welch's 
recollections of home treatment for haemophiliacs at that time are written in a letter to 
Dr Daphne Christie, 5 July 1999, and will be deposited with the records of this meeting in the 
Contemporary Medical Archives Centre of the library of the Wellcome Institute for the 
History 
of Medicine. 



36 



Haemophilia: Recent history 

to say that now, but we are talking about 30 years ago. It was for the doctor to 
say when patients needed treatment. That's one of the reasons the children of 
that generation grew up crippled with haemophilic arthritis. 117 

There wasn't enough plasma being collected. When cryo [precipitate] came 
in there was just enough to be able to perform outpatient treatment, there wasn't 
enough for home therapy. There wasn't enough plasma going through to the new 
Elstree site to make concentrate and that was one of the reasons why the 
Government decided to bring in concentrate, particularly from the United 
States of America. This decision should be seen against the background of a 
very, very rare disorder in the multitude of medical conditions, and the 
resistance that there was to the treatment which had been developed in Oxford, 
and to allowing patients to start treating themselves. 

Mrs Riva Miller: 118 I am from the Royal Free and I very much appreciated 
Dr Evans's talk, because it certainly reminded me that in 1958 I was at the 
Manchester Royal Infirmary and worked on the Leukaemia Unit, so I had some 
connections back there. Let us come back to Dr Dormandy and home treatment. 
She employed me in 1966 to look into the home circumstances of all the 
patients, particularly the children and how much they missed school, to see 
whether we could start to think about home treatment. That was an enormous 
survey which really had quite an impact. 119 It was Dr Tuddenham's foresight 
and persistence that secured a position to look into all the other needs of 
people, that helped me to stay there until today, although that position is being 
dismantled now. 

EvanS: I want to contradict Peter Jones, because I worked in a children's 
hospital and I think actually it's very different in children's hospitals. At the 
time we were introducing home treatment, we were positively encouraged by 



117 Dr Peter Jones wrote: 'There was no treatment at home and the parents were usually very- 
reluctant to take them to hospital'. Letter to Dr Daphne Christie, 5 July 1999. 

118 Riva Miller (b. 1935) is a social worker and a trained family therapist with particular 
interests in HIV/hepatitis and close involvement in orthopaedic clinics, and has worked in the 
Royal Free Hospital Haemophilia Centre since 1966. Her main interest has been in 
integrating the social, psychological and medical aspects of the lives of people with 
haemophilia and their families into the day-to-day work of the Centre, particularly in busy 
clinics. She currently runs the AIDS Counselling Unit at the Royal Free NHS Trust and has a 
consultancy at the Blood Service in North London. She has worked for the World Health 
Organization running workshops for haemophilia and AIDS. 

119 Rizza C, Spooner R J D. (1977) Home treatment of haemophilia and Christmas disease: five 
years' experience. British Journal of Haematology 37: 53-66. idem (1983) Treatment of 
haemophilia and related disorders in Britain and Northern Ireland during 1976-80; report on 
behalf of the directors of haemophilia centres in the United Kingdom. British Medical Journal 
286: 929-933. 



37 



Haemophilia: Recent history 

everyone to do so. We were appointing nurses to look after children with cystic 
fibrosis at home, nurses to look after children with diabetes at home, and as 
soon as I wanted to introduce a home treatment programme I was encouraged 
to do so and I was provided with a nursing sister to help do it. I think that was 
the difference between adult centres and the children's hospitals, which were 
quite independent. The second thing, of course, about cryoprecipitate for home 
treatment is that little children only need little doses, so it was much easier for 
the parents to be trusted to draw up a few bags of cryoprecipitate rather than the 
enormous number of bags that you have to do for an adult. 

Colvin: I wanted to say a couple of words in support of what Riva [Miller] 
was saying, and to mention Katharine Dormandy's influence on trying to 
provide comprehensive care for all the children, and indeed, adults, in the 
North-East Thames region. "When Professor Jenkins 120 was Director of the 
London Hospital Haemophilia Centre, he and Katharine got together in the 
early 1970s and organized a haemophilia nurse to go round the whole of our 
huge region, seeking out people with haemophilia and that was really the 
beginning for us of the idea of having a home treatment programme on a large 
basis. I think it is important to know that Katharine, just before she died, made 
a really big impact on finding out just exactly who'd got haemophilia in our 
region and set up the possibility of treating them all, instead of just some of 
them. 

Lee: In my room in the hospital I found a book which has got the minutes of 
those meetings and what is so amazing is that there is an account of the number 
of bottles of concentrate that were being issued in the region: they are minuscule 
amounts. One of the things that Charlie [Rizza] was talking about the other day, 
was that you got as many bottles as your local transfusion centre provided the 
plasma for. 

Rizza: Yes, there was a time when the factor VIII produced by Elstree was 
delivered pro rata to the different Haemophilia Centres, so that if a region put 
in large amounts of plasma centrally to be fractionated, it got large amounts of 
factor VIII back to the Haemophilia Centre. If the region put in only a small 
amount of plasma to be fractionated centrally, then that region got a very small 
amount of factor VIII. That made difficulties for some large centres which had 
Blood Transfusion Centres which were not giving large amounts of plasma 



120 Professor George Jenkins FRCP FRCPath (b. 1927) was Consultant Haematologist at 
the Royal London Hospital from 1965 to 1992 and President of the British Society of 
Haematology in 1988. 

38 



Haemophilia: Recent history 

through central organizations for fractionation. I think that system has now 
fallen into disrepute. 

Lee: We have heard so far this afternoon only from the people who were giving 
out the care. We haven't really heard much of the history of things from the 
people who were receiving the care. I wonder if I could encourage some 
comments about that? 

Reverend Alan Tanner: 121 I am very interested in the saying of Gwyn 
Macfarlane, 'One has to remember what it was like not to know things which 
now seem self-evident', because, I think, testifying from the point of view of a 
father of a patient, it is worth remembering the change in attitude and lifestyle 
which took place at these various stages. I was very interested to hear the 
mention of 'comprehensive care', which was one of the major advances in 
treatment, care management and so on. But going right back to the beginning, 
some have heard me testify before about my introduction to haemophilia with 
Professor Hardisty, because my own son was diagnosed at Great Ormond 
Street. Then, as I have said many times, there was no treatment except Russell's 
viper venom. 123 Russell and the viper have been much maligned in the past, but 
were of great comfort in moments of crisis. 

Lee: We are talking about 40 years ago, aren't we? 

Tanner: Yes I am going right back - 40 years. The facilities provided were 
minimal. Russell's viper venom for crises, plasma, a pat on the back, tender 
loving care and all that. So we need to remember the transformation which 
came with the introduction of cryoprecipitate. I am a Royal Free Hospital 
supporter, so I can speak again about Dr Katharine Dormandy. One of the things 
we haven't mentioned yet is that Dr Dormandy introduced boys to treating 
themselves at a very, very early age. When parents thought they were taking over 
the management of injecting cryoprecipitates, Dr Dormandy was very firm: the 
boys were going to exercise that sturdy independence, and begin to treat 



121 The Reverend Prebendary Alan Tanner (b. 1925) was Chairman of the Haemophilia Society 
from 1976 to 1997, Chairman of the World Federation of Hemophilia from 1973 to 1995 and 
Chairman of the Macfarlane Trust since its foundation in 1988. He has three daughters and 
one son who was diagnosed with haemophilia at the age of five in I960 and died in 
October 1998, as a result of HIV infection and hepatitis C virus (HCV) through the use of 
contaminated blood products. 

122 See biographical note 73 above. 

123 op. cit. note 19 above. 

39 



Haemophilia: Recent history 

themselves and that was when they began, as it were, to wean themselves from 
centres, doctors, and all that. So that's cryo [precipitate] for a start. 

It was round about that time that we obviously looked to Oxford for the 
kind of academic support in these endeavours, and at the same time I have to 
pay tribute to Professor Ingram who was my mentor in those days. I often 
remember he was the one whom I asked, 'How do you say amniocentesis?' He 
told me and explained what it meant, and that was another part of my tutoring 
in the whole endeavour. And then, as we have mentioned, with the introduction 
of concentrates, that was where comprehensive care came in. Dr Jones won't 
mind my mentioning the transformation that took place at his centre when he 
took over Newcastle. He was one of the first to introduce comprehensive care 
with a team which included an orthopaedic surgeon, a dental surgeon, 
physiotherapists, social workers and so on. He developed what we used to call 
the 'heavy gang' in Newcastle, which, I think, he took on tour to show how it 
could be done. So then again, it's a transformation taking place, not only in a 
physical sense, but in that development of independence, and in emotional 
maturity, because for the boys and men, when they were introduced to these new 
concepts of treatment and management, their lives were transformed. Where 
they had previously been tied to a centre, they then began to travel. I speak from 
experience of those who came to the World Federation of Hemophilia; 124 they 
were released, made free, and there was a tremendous sense of liberation. 

We then go onto the other stages with the introduction of HIV infection 
and hepatitis, and now possibly CJD. That's a sad part of the drama, but up to 
that stage there was that very, very significant transformation of life. I could 
speak forever about that, but I think that's probably enough to emphasize the 
points. 

Mr Clifford Welch: 125 I was born in 1925 and haemophilia was diagnosed 
when I was a year old by my falling out of my highchair and tearing the 
fraenum in my upper lip. Thereafter, very fortunately, I had a perfectly normal 
life, having only mild haemophilia, so I enjoyed my school days, but life at 
home was really severely shook up when, at the age of five, my mother 
produced triplets who also had haemophilia and it was that which brought us 
into contact with Professor Macfarlane, Dr Macfarlane as he then was, at Bart's. 
It was in 1934 when one of my brothers was admitted to Bart's with a severe 



124 For an account of the history of Haemophilia Societies and the World Federation of 
Hemophilia, see note 5 above, 12-13 and note 169. 

125 Mr Clifford Welch CBE FIM (b. 1925) trained as a materials engineer. He also pursued a 
career in scientific and technical publishing, and served on the Design Council from 1993 to 
1998, latterly as Chairman. He has been associated with the Katharine Dormandy Trust for over 
20 years and Chairman for the majority of that time. 



40 



Haemophilia: Recent history 

haemorrhage and, I think, two of them were treated there for long periods. We 
also used to go up and see Gwyn Macfarlane regularly every few months while 
he took blood tests. After he retired I remember getting a letter from him in 
which he said how he watched his delicate apparatus in his small room at Bart's, 
most of which was constructed from Meccano, 126 being crawled over by my 
three brothers like monkeys, wondering whether it was all going to get torn to 
pieces or not. But he was really a wonderful supporter to my mother, because at 
that time in the 1930s there really was, as Alan Tanner has said, no treatment 
other than the Russell viper venom. I can remember cycling to John Bell and 
Croyden in Wigmore Street 127 on a Sunday to get Russell viper venom for one 
of my brothers with a serious external bleed. But apart from that the real 
miracle was Macfarlane introducing the concept of blood transfusions from my 
mother to the boys, which, of course, in the late 1930s saved their lives on a 
number of occasions. 128 Then in 1941, or 1942, we came into contact with Frank 
Smith 129 who was one of the early members of the Haemophilia Society. He 
had a flat off Baker Street and I can remember going to one of the first 
meetings of the Society with my mother in an air raid and listening to him 
explaining that the only sure treatment was Dr Timperley's egg white 130 and 
this was very seriously propagated by him for many years afterwards. It was a 
tragedy because despite his deep concern that Dr Timperley's work did not 
meet with success, Frank Smith made a major contribution to getting the 
Haemophilia Society going. But as far as I was concerned I had a charmed life 
really, and the only time I was seriously injured I was cared for in Bart's, 
during the war, when Dr Black and Charles Fletcher looked after me with 
advice, I gather, from Dr Macfarlane, who by then was 
at Oxford. 

Lee: Last week when we went to interview Dr Rosemary Biggs, 131 I asked, 
'What was Macfarlane doing all the time? Was he locked up in the laboratory, 



126 Macfarlane devised a number of apparatus, in part made of Meccano. See for example 
Robb-Smith A (1993) op. cit. note 3 above, 51. Macfarlane R G, Tomlinson A H. (1961) 
An apparatus for measuring the tensile strength of blood clots. Journal of Clinical Pathology 
14:320-323. 

127 John Bell and Croyden was a well-known pharmacy in London. 

128 op. cit. note 20 above. 

129 Frank Smith was one of Macfarlane's haemophilic patients and main organizer of the 
International Haemophilia Society. 

130 That is treatment with a bromide extract of egg white. Timperley found that if egg white is 
incubated at 37°C with potassium bromide for several days it was possible to extract a substance 
which on intravenous or intramuscular injection reduces the clotting time of blood and 
controls haemorrhage in haemophiliacs. See Timperley W A, Naish A E, Clark G A (1936) A 
new method of treatment in haemophilia. Lancet'n: 1142-1149. See also page 53 below. 

131 op. cit. note 2 above. 

41 



Haemophilia: Recent history 

or did he get involved with the patients at all?'; and Dr Biggs replied, 'No, he 
didn't really get into our first patients. There were one or two patients he 
remembered from St Bartholomew's Hospital. One I remember was a set of 
triplets with haemophilia (that is, Clifford's brothers)'. And then I went on to 
explain what has happened to them since and she rounded off the conversation, 
'...They weren't angels, they were absolutely all over the place. I know 
Professor Macfarlane had them in Bart's when they were three or four and he 
said they were absolute menaces about the laboratory'. But it's interesting that 
you talk about the Meccano, because I have another patient who remembers 
Macfarlane from Bart's and keeps talking about this Meccano that was 
presumably shaking the tubes for the tests. 

Douglas: Since you returned to Dr Biggs' earlier recollections, it is 
appropriate to give my reminiscences of Oxford between 1951 and 1953 at this 
stage. My time in Oxford preceded the major later endeavours to treat 
haemophilia. I had the enormous privilege of working with Gwyn Macfarlane, 
Rosemary Biggs and Ethel Bidwell. This experience shaped my academic 
interest in haemostasis and thrombosis after I left Oxford. My initial ignorance 
was a shock to Rosemary and Ethel, but after a few months of their training I 
was ready to do experiments. In the work which followed my name appears on 
several papers; 132 my name is there because I helped to do a lot of experiments 
but the ideas for these came from Dr Macfarlane and Rosemary Biggs. I arrived 
in Oxford at a time when there was about to be a breakthrough from their 
previous experimental work, especially their study of thrombin generation from 
whole blood. 

I had some earlier interest. In 1944, on my first day as a house physician 
after graduation, a teenage haemophiliac had a single tooth extracted and the 
socket bled for three weeks after. Three years later a severe haemophiliac, who 
had been under my care, died from coronary thrombosis. This taught me that 
thrombosis was not entirely due to blood clotting. 

I have quoted reminiscences here. I still remember a lot of things 
Macfarlane said, such as, 'Reminiscences are only really of interest to those who 
are telling them,' but more importantly, and it's already been quoted today, 
'One has to remember what it was like not to know things which now seem self- 
evident'. 133 



132 See for example Biggs R, Douglas A S, Macfarlane R G. (1953) The initial stages of 
blood coagulation. Journal of Physiology 122: 538-553. Douglas A S, Biggs R. (1953) 
Consumption of some components involved in physiological blood coagulation. 
Glasgow Medical Journal 3A: 329-342. See also note 17 above. 

133 See also Reverend Alan Tanner's recollections on page 39 above. 



42 



Haemophilia: Recent history 

And in 1951 we did not know much. We knew using Quick's one-stage 
prothrombin time test that citrated or oxalated plasma clotted on the addition 
of tissue extract and calcium. 1 Some years later Quick noted when oxalated 
plasma was left standing on the bench, the clotting time of this plasma in his 
test lengthened; he assumed this to be a 'labile factor'. 135 Working in Norway 
during the war, Owren described a genetic coagulation defect with a prolonged 
one-stage test not due to prothrombin deficiency. 1 This was called factor V 
and was the same as Quick's 'labile factor'. We also knew at around that time 
that there was another factor involved and that was factor VII. 137 It had been 
shown in the late 1940s that normal serum (containing no prothrombin nor 
factor V) shortened the one-stage test of coumarin plasma. 138 This led to the 
discovery of factor VII. 

Up to 1951 coagulationists had been mainly concerned with the action of 
tissue which produced rapid coagulation of blood. However, it was known that 
blood collected by clean venepuncture without tissue contamination did 
coagulate, albeit more slowly. This unknown intrinsic pathway for clotting had 
been neglected too long and its time came in Oxford in 1952. Previous studies 
had shown that normal blood delivered to a glass tube coagulated in five to ten 
minutes and that prothrombin was rapidly consumed. In haemophilia and 
thrombocytopenia, prothrombin consumption was defective and the plasma 
factor missing in haemophilia (so-called antihaemophilic globulin), and 
platelets were likely to be two components of an intrinsic pathway. 139 



134 According to the classical theory of coagulation, prothrombin was converted to thrombin 
and thrombin clotted fibrinogen (see Appendix). Quick A J. (1935) The prothrombin in 
hemophilia and in obstructive jaundice. Journal of Biological Chemistry 109: lxxiii-lxxiv. 
Quick A J, Stanley-Brown M, Bancroft F W. (1935) A study of the coagulation defect in 
hemophilia and in jaundice. American Journal of the Medical Sciences 190: 501-511. 

135 Quick A J. (1943) On constitution of prothrombin. American Journal of Physiology 
140:212-220. 

136 Owren P A (1947) Coagulation of blood: investigations on a new clotting factor. Acta 
Medica Scandinavica 128: 1-327. 

137 de Vries A, Alexander B, Goldstein R. (1949) Factor in serum accelerates conversion of 
prothrombin to thrombin: its determination and some physiologic and biochemical 
properties. Blood A: 247-258. Koller F, Loeliger A, Duckert F. (1951) Experiments on new 
clotting factor (factor VII). Acta Haematologica 6: 1-18. 

138 Fahey J L, Olwin J H, Ware A G. (1948) Effect of dicoumarol on Ac-globulin and 
prothrombin activity. Proceedings of the Society for Experimental Biology 69: 491-494. 

139 Dr Charles Rizza wrote: 'Blood coagulation can proceed by the intrinsic or extrinsic 
system, two separate but interlinked routes. In the intrinsic system only the plasma coagulation 
factors are involved. In the extrinsic system tissue factor plays an important role (see Appendix). 
In haemophilia the intrinsic system is defective because of lack of factor VIII, an essential 
component. The fact that haemophilic tissue (brain) when added to haemophilic blood brought 
about normal clotting was evidence that haemophilic tissue was normal and that the 
haemophilic-clotting defect was due to a failure of the intrinsic system.' Letter to Dr Daphne 
Christie, 3 July 1999. 

43 



Haemophilia: Recent history 

Before I arrived in Oxford I had worked in Glasgow Royal Infirmary, 
where the brain from a patient who had died of haemophilia was as powerful as 
normal brain in clotting haemophilic plasma. The extrinsic pathway in 
haemophilia 
was intact. 

Early in 1952 another important patient was studied, and in my way of 
thinking was more important than the Christmas factor-deficient patient, 
studied five months later. The patient was under the care of Professor L J Witts 
in Oxford. He was a 26-year-old man who had an acquired coagulation 
defect with bruising epistaxis [nose bleed], gum bleeding and haematuria. He 
had a one-stage prothrombin time of 18-22 seconds compared to a normal 
plasma result of 14 seconds. When brain was added to his plasma and this then 
recalcified, thrombin developed immediately, but it was very little compared 
to that from a normal plasma. Rosemary [Biggs] had the foresight to do 
critically important experiments on this plasma, and I can still remember her 
doing these experiments. She diluted this plasma, recalcified it and then took 
aliquots using them in lieu of brain in a one-stage prothrombin time and finding 
as powerful thromboplastic activity as brain, developing after four to five 
minutes incubation. At the same time she subsampled on to fibrinogen and 
found no important amounts of thrombin. On 20 February 1952 she posted a 
letter to Nature which records her personal contribution to the enormous 
discoveries that were made in that year and launched a whole new era of blood 
coagulation research. 1 ' 

Two simple plasma fractionation procedures were in use. When alumina 
was added to plasma this removed prothrombin and factor VII leaving, after 
centrifugation, factor V and antihaemophilic globulin in the supernatant 
'adsorbed plasma'. After centrifugation, elution from alumina precipitate 
recovered prothrombin and factor VII. A second fractionation method was 
ammonium sulphate precipitation producing crude preparations of factors V 
and antihaemophilic globulin. Platelets were prepared by differential 
centrifugation. Rosemary made a preparation of antihaemophilic globulin from 
ammonium sulphate precipitation of adsorbed normal plasma and a factor VII 
preparation from adsorption of serum, and when she incubated these three with 
calcium a powerful thromboplastin was formed. 



140 Professor Leslie J Witts (1898-1982) was Nuffield Professor of Clinical Medicine at 
Oxford from 1938 to 1965 and a Fellow of Magdalen College. From 1963 to 1968 he was a 
member of the Committee on Safety of Drugs and Chairman of the Subcommittee on Adverse 
Reactions. 

141 Biggs R. (1952) Plasma thromboplastin. Nature 170: 280. 
42 Details of the plasma fractionation procedures are given in Biggs R, Macfarlane R G. 



(1953) op. cit. note 37 above, 71 and 343. 

44 



Haemophilia: Recent history 

Following the findings described in Nature in early 1952, we used diluted 
adsorbed normal plasma as a source of antihaemophilic globulin, diluted 
normal serum as a source of factor VII and washed platelets with calcium to 
make a powerful thromboplastin. This became the work-up of the 
thromboplastin generation test. 

In June 1952 we submitted a manuscript on the formation of 
thromboplastin in human blood to the Journal of Physiology. 1 3 It was published 
early in 1953 by which time we knew that the property of serum was not due 
solely, if at all, to factor VII. 

The early features of the thromboplastin generation test were the 
abnormality present in the adsorbed plasma in haemophilia, and the abnormal 
behaviour of coumarin serum (initially attributed to factor VII). Also 
circulating anticoagulants could be detected, and abnormal platelet function in 
'thrombasthenia' demonstrated. 

Then one day in July 1952, I was asked to apply the thromboplastin 
generation test to two haemophiliacs where Merskey's 'plasma mixing 
experiments" had shown cross-correction. One of the blood samples came 
from John Dacie and Bob Pitney at the Hammersmith Hospital [the patient was 
Stephen Christmas] and the second was an Oxford patient previously studied 
by John Poole. 145 Their adsorbed plasma behaved normally in the test but their 
serum was abnormal. 

The test therefore provided a method for telling the two 'haemophilias' 
apart and provided immediately a worldwide reference to help differentiate 
the two disorders. When seven patients had been collected, from amongst 
previous postgraduate students at Oxford, including Clarence Merskey, the 
'new' disorder was published in the British Medical Journal in December 
1952. One of the families described revealed a sex-linked recessive type of 
inheritance, making the two disorders not only clinically but genetically 
similar. 

The thromboplastin generation test became important not only in the 
laboratory diagnosis of clinically suspected bleeding disorders, but was 
modified to produce assay techniques for antihaemophilic globulin (factor 
VIII) and Christmas factor (factor IX), these being essential in the therapeutic 
endeavours which developed later. We published two other papers on the 



143 Biggs R, Douglas A S, Macfarlane R G. (1953), op. cit. note 17 above. 

1 op. cit. notes 35 and 36 above. 

1 5 See biographical note 33 above and Sir Christopher Booth's contributions below. 

1 6 op. cit. note 1 8 above. 



45 



Haemophilia: Recent history 

intrinsic pathway in the Journal of Physiology. w Factor V as well as factor VIII 
in the adsorbed plasma were shown to be needed. Dr Macfarlane often talked 
about an amplifier and we did some experiments realizing that all the known 
components (factors V, VII, VIII, IX and platelets) were unlikely to react 
together simultaneously. Our reagents were too impure to make significant 
progress and it was not until 

ten years later that Gwyn Macfarlane recognized his amplifier to be an 
enzyme cascade. 



1 148 

ide 



Sir Christopher Booth: 149 I think I should, as a historian of the 
Hammersmith Hospital, inject two of Hammersmith's contributions into this. 
The first is that after Gwyn Macfarlane went to work at Hammersmith, from 
1935 until the war, he wrote his thesis on disorders of the clotting mechanism 
for which he obtained a gold medal of the University of London. 150 I found that 
thesis when I was writing my own thesis in the 1950s and I modelled my thesis 
on his. I am happy to say that I got a gold medal too. But that isn't what I 
wanted to say. The point about the Christmas case was that the original case was 
a patient of the late Sir Graham Bull, 151 who attended at Hammersmith with 
bleeding of the tongue, this boy having bitten his tongue. And it was that 
patient, referred to Professor John Dacie's department, on whom W R Pitney 152 
did a thromboplastin generation test 153 which came out wrong, and he couldn't 
understand it. So he went down to see John Dacie and it was Dacie, who knew 



147 Biggs R, Douglas A S, Macfarlane R G. (1953) op. cit. notes 17 and 132. 

148 Macfarlane R G. (1964) An enzyme cascade in the blood clotting mechanism, and its 
function as a biochemical amplifier. Nature 202: 498-499. idem (1966) The basis of the 
cascade hypothesis of blood coagulation. Thrombosis et Diathesis Haemorrhagica 15: 591-602. 

1 9 Sir Christopher Booth Kt FRCP (b. 1924) trained as a gastroenterologist and was Director 
of the Clinical Research Centre of the Medical Research Council, from 1978 to 1988. He was 
the first Convenor of the Wellcome Trust's History of Twentieth Century Medicine Group, 
from 1990 to 1996, and Harveian Librarian at the Royal College of Physicians from 1989 to 
1997. 

150 Macfarlane R G (1938) The normal haemostatic mechanism and its failure in the 
haemorrhagic states. MD thesis, University of London. 

151 Sir Graham Bull Kt FRCP (1918-1987) joined the Postgraduate Medical School in 
Hammersmith in 1947. He was appointed to a lectureship in the Department of Medicine and 
later was in charge of the renal unit where he developed a treatment that became renowned f o r 
its use in the acute phase of renal failure. He served as a member of the Medical Research 
Council from 1962 to 1966 and was appointed director of the Medical Research Council's 
Clinical Research Centre at Northwick Park in 1966. He was second Vice-President of the 
Royal College of Physicians from 1978 to 1979. 

132 Professor W R Pitney ('Bob' mentioned on page 45) (1921-1986) carried out research into 
blood disorders at the Royal Postgraduate Medical School in Hammersmith, London, and was 
Dean of the Faculty of Medicine at the University of New South Wales from 1984 to 1986, and 
President of the 21st International Congress of Haematology in 1986. Much of his research 
work focused on coagulation factors (see also notes 18 and 39). 

153 op. cit. note 17 above. 



46 



Haemophilia: Recent history 

the literature extremely well, being a great scholar, and knew about the South 
American paper 154 and said, 'Go and do it again'. Following that they got in 
touch with Rosemary Biggs and Macfarlane and that resulted in the original 
Christmas paper in the Christmas issue of the British Medical Journal in 1952. 155 
And it was interesting also that people like Dacie, Rosemary Biggs and Gwyn 
Macfarlane were not the sort of scientists who fought with each other for 
priority. If they had a problem they got together and that's exactly what 
happened over Christmas disease. It's a very good message 
to us all. 

Lee: I think there's another twist of the tale of Mr Christmas. Rosemary 
Biggs 156 told me that nobody believed that his name was Christmas for a start, 
because it happened to appear in the Christmas edition of the British Medical 
Journal 57 and they thought it had all been made up. The rather sad thing, which 
probably summarizes what we have been talking about in the first part of this 
afternoon, is that I recently was participating in a meeting with a physician 
from Canada, called Jerry Teitle, who looked after Mr Christmas in his last 
years. Mr Christmas died a few years ago of HIV and I think that really 
illustrates what a short time span we are considering: first the disorder was 
described, the treatment was evolved, and the poor man actually died from the 
side-effects of that treatment. We are going to have to break for tea now in the 
next room, where there are some amazing photographs of Dr Bidwell in her 
younger days with her assistant Ross Dike (Figures 1-8). It's due to Mr Dike 
that we have these beautiful photographs, because when the laboratory was being 
tidied up at Oxford, he rescued them and put them in his loft. 

Ingram: Just before we go may I finish the story about the name of Christmas 
disease? A gentleman from Leeds wrote to protest at this, and so Biggs and 
Macfarlane wrote back in the next British Medical Journal 5 * to say that if they 
hadn't used that name they would have made up an enormously long name 159 
which was much less easy to deal with, but they gave an undertaking that if they 
found a precursor factor they would not call it Christmas Eve factor! 



15 See note 16 above. 

155 op. cit. note 18 above. 

156 op. cit. note 2 above. 

157 op. cit. note 18 above. 



158 See Collins D H. (1953) Christmas disease. British Medical Journal i: 97. Kemp P R. ibid. 
Biggs R, Douglas A S, Macfarlane R G. ibid. 221. 

159 Hypoprothromboplastinogenaemia. 

47 



Haemophilia: Recent history 

EvanS: I also wanted to make one little comment, to remind some of the 
people who aren't as old as the rest of us, that in those days when you had to go 
to the slaughterhouse to get reagents to do laboratory work, you also had to 
make your own apparatus. You couldn't go and buy an amino-acid analyser, or a 
gas chromatograph off the shelf, you had to get the parts yourself and put it 
together and that's what the bits of Meccano were referring to. If you wanted 
to make a chromatograph, you had to go to the workshop and get a tube, and cut 
it to the length you required, and that I think is worth remembering. 

Lee: Can we now look at more of the organizational aspects of haemophilia 
both from the healthcare delivery side, the UK Haemophilia Centre Directors 
Organization, its beginnings, and the Registry at Oxford. Also the 
Haemophilia Society and how it grew up and how it interrelated with the 
Haemophilia Centre Directors Organization, and the delivery of care. 
Although we are primarily thinking about haemophilia in the context of Britain, 
we have to think a little bit about the influences that Britain had on the World 
Federation of Hemophilia, because they were quite significant. We are also 
going to discuss what we really don't like to think about too much, but sadly 
have to think about a lot, and that is the contamination that blood products have 
brought upon the haemophilic population and the enormous change in so many 
ways that that has influenced. Then, finally, because I think it would be so sad 
to end this afternoon 



1 See note 126 above. 



48 



Figures 1-8. Preparation of animal antihaemophilic globulin in 1955 




1. Animal blood is collected at the slaughterhouse and brought to the laboratory by Ethel Bidwell and her assistant Ross Dike. 




2. The blood is centrifuged to separate plasma from the red cells. 




3. Plasma is removed by suction. 




4. The plasma is again separated by centrifuging. It is cooled and the active factor is precipitated by adding phosphate bujfer. 



II1E 8 2» 



..,:.-. 

«*:| 




5. The purification ts carried a stage further by another precipitation, with sodium citrate. 

r**WK — If 

2L 




6! The precipitate is collected by centrifuging and the supernatant fluid containing impurities is discarded. The precipitate is dissolved in saline. 




7. Most of the addec 



I to the instability of material, this must be done rapidly. The apparatus is shown. 




8. Preservation by freeze-drying. 



Photographs kindly provided by Mr Ross Dike, processed and mounted by him. Permission granted to reproduce photographs, 
Dr Ethel Bidwell and Mr Ross Dike, 1999. ©Mr Ross Dike, 1999. 



Haemophilia: Recent history 



on a dismal note, I want to focus a little bit of attention on the early 
development of recombinant products which, of course, is what we all want to 
treat our patients with in 1998. I am going to ask Dr Rizza to try and set the 
scene. How did the Haemophilia Centre Directors Organization come about? 

Rizza: Before tea Clifford Welch talked about treatment as it was in the 1930s 
and the 1940s and he mentioned Timperley's egg white and a patient called 
Frank Smith. Timperley's egg white were little tablets, these [holding 
some] the date of which, I think, was 1949. A bit out of date now. I am going 
to be provocative and suggest that, in fact, this is to some extent important in 
the development of haemophilia care, because Mr Frank Smith, and some other 
haemophiliacs at that time, were very conscious of a lack of treatment or any 
support for haemophilia. I know Mr Smith made a nuisance of himself — he 
wouldn't mind me saying that - by going to the Ministry of Health on many 
occasions, and to the Medical Research Council, asking them to make this very 
important material [i.e. Timperley's egg white]. But they could never find any 
scientific evidence for putting any effort into that, so he began to make it in his 
kitchen at home. My recollection is that this material required fuming 
hydrobromic acid for its manufacture from egg albumin and on one occasion it 
blew up in his face in the kitchen and he was scarred for life thereafter because of 
his acid burns. But I think the consequence of the inception of the National 
Health Service, and people like Frank Smith constantly asking for help, was 
that Sir Weldon Dalrymple-Champneys, 162 who was a Deputy Chief Medical 
Officer, wrote to Professor Macfarlane in Oxford and to Dr Wilkinson 163 in 
Manchester suggesting that something should be done for haemophiliacs. The 
time had come to sit down and make plans. So they had a little meeting, a very 
informal meeting in early 1950, and thereafter several meetings were held with 
other interested doctors. They wrote around to find out who was interested in 
haemophilia and they got a small group together and they began holding more 
formal meetings to discuss what could be done. And of course in those days 
there was nothing that could be done really. There weren't even diagnostic tests, 
or at least reliable ones. So they agreed that they should give advice to the 
patients on how best to help themselves, advice to the GPs on how best to help 
the patients and also to educate the general public, and in particular employers, 



161 op. cit. notes 129 and 130 above. 

162 Sir Weldon Dalrymple-Champneys FRCP (1892-1980) was President of the Haemophilia 
Society for 27 years. He joined the medical staff of the Ministry of Health in 1927 and became 
Deputy Chief Medical Officer in 1940. 

163 op. cit. note 76 above. 

53 



Haemophilia: Recent history 

about the needs of haemophiliacs. And that's how it started and I like to think 
that it probably started because of the insistence by some patients on the value 
of this material, egg white. 

Thereafter, the organizing group became larger, and it was agreed that 
certain regions should have centres to look after haemophiliacs. The MRC got 
involved in the early 1950s and promoted and funded work on the manufacture 
of factor VIII. Thereafter, the Ministry of Health took over the organization of 
care, but all the time there was a nucleus of centres in regions throughout the 
country who were offering care of a kind. It was mainly supportive, there was 
no therapeutic material available, but they were getting together the core of 
an organization. 

As time went on and factor VIII became available more widely, 
especially by 1 972 when the first large pool concentrates began to come into the 
country, it was seen then that there was a need to formalize the organization of 
the care a little more. In 1968 the first meeting of doctors who were interested 
in haemophilia met in Oxford. There were 26 doctors who turned up and we 
had an afternoon party and, I think, there were one or two lectures given, a lot of 
exchange of ideas, and exchange of worries about haemophilia care, and the 
feeling was that really this was so useful that we should meet every year 
thereafter to discuss the problems of haemophilia. Simple things like how 
many staff you require to look after 100 patients or 50 patients, what services, 
what nurses do you require. This is how it started in 1968 and since then, yearly, 
the Directors of the Haemophilia Centres up and down the country have met at 
different places around the UK just to do what I have said: discuss problems, 
learn from each other and from people from abroad. Eventually scientific 
sessions were built in so that foreign experts could come and tell us what was 
happening in other parts of the world, and this was the way the organization of 
haemophilia care in this country started. 

Lee: Can you tell us when the Registry first came about? 

Rizza: In 1968, right after the first meeting. After the first meeting it was felt 
that without information on the numbers of patients, what kind of treatment was 
being used up and down the country, what kind of complications were being 
met, how many cases were dying, it would be very difficult to promote better 
care and better organization and so on. So from the very early days annual 
returns (Rosemary Spooner is here, she helped to set it up) were received from 



54 



Haemophilia: Recent history 

all the Haemophilia Centres in the country. They were analysed, reports were 
written, and those reports were sent back to the different Haemophilia Centres, 
as well as to the Department of Health and to the fractionation laboratories. 
The fractionation laboratories had to know the size of the problem as they were 
going to be manufacturing the concentrates necessary for treatment. The 
Registry has been going for 30 years now. 

Lee: In the interview with Dr Biggs last week, she described in vivid detail 
this first meeting and she said, 'Well I decided to have a party. Everybody 
likes to come to a party. And I invited to this party everybody who knew 
anything about haemophilia at that time. I was a lady, and ladies were allowed 
to organize parties.' And the other thing was when we went on to talk about the 
organization and having a chairman and things, she said, 'I was never the 
chairman, I don't think there is any point in being a chairman. Chairmen don't 
have any power. The power resides in the person who writes the minutes, and I 
write very good minutes.' 1 5 Now can you perhaps, Alan, tell us when the two, 
the Haemophilia Society and the Organization, interacted. 

Tanner: Yes, that was at the beginning as Dr Rizza says. He mentioned the 
name of Sir Weldon Dalrymple-Champneys who was a key person in 
encouraging people with haemophilia to come together to meet for mutual 
support, sharing views about treatments or the paucity of treatments, to help 
each other in terms of financial support if that seemed to be necessary. Those 
small beginnings in the 1950s were mostly in people's houses, just a small 
number getting together. It began to expand and eventually in the 1960s they 
thought about looking for some kind of base where they could congregate much 
more frequently and have an office from which they could operate. So the older 
members, the old hands, will recall the famous fire station in Southwark. It was 
surplus to requirements, let me add, it was a building which was made 
available, and that was the beginning of an organization for the Haemophilia 



16 Rosemary Spooner (b. 1937) was Secretary to the MRC Blood Coagulation Research Unit 
from 1961 to 1967 and Secretary/Research Assistant to Dr Rosemary Biggs, at the Oxford 
Haemophilia Centre from 1967 to 1977. Since 1977 she has had an NHS appointment as 
Research Assistant/Data Analyst at the Oxford Haemophilia Centre and has been Honorary 
Administrative Secretary to the United Kingdom Haemophilia Centre Directors 
Organization since 1988. She is co-author to several publications including Biggs R, Spooner 
R J D. (1977) Haemophilia treatment in the United Kingdom from 1969 to 1974. British 
Journal of Haematology 35: 487-504. idem Haemophilia Centre Directors' annual statistics for 
1975. ibid. 36: 447-449. idem (1978) National survey of haemophilia and Christmas disease 
patients in the United Kingdom. Lancet'v. 1 143—1 144. 

165 op. cit. note 2 above, 770. 

166 See biographical note 162 above. 

55 



Haemophilia: Recent history 

Society, manned entirely by volunteers and that was a very, very important 
aspect of the whole organization. It was done by volunteers supporting each 
other and beginning to become rather aggressive in their style in relating with 
their doctors and dealing with the Government and so on. They began to 
organize one or two campaigns, and now the society is well organized as a 
campaigning body. 

One of the first campaigns they ran was to do with the provision of 
transport. There was some deadly mechanism which some will recall. It was a 
tricycle which was made available for those who were disabled and it was 
lethal. They managed to get none other than Graham Hill, who was quite 
famous as a racing driver then, who took his life in his hands by testing it. They 
assembled together MPs and Graham Hill drove this erratically so that it 
overturned and so he was able to demonstrate that it was not suitable for people 
with haemophilia. That was the beginning of that kind of campaigning 
movement. Volunteers were operating from this old fire station, which was a 
good place to meet and to lodge papers, because by then they began to 
accumulate a certain amount of files and papers and so on. 

The next move was when the lease of that dilapidated building expired, 
and they moved into much more palatial surroundings in Trinity Street in 
Southwark, which many will remember, again run entirely by volunteers. But the 
Organization was developing to such a degree there in the 1 960s that they found 
it was no longer satisfactory for people to be keeping papers at home; letters 
got lost and were never answered, so they managed to recruit a part-time 
secretary, Irene Watson, who came in two mornings a week to deal with the 
correspondence. Then, moving on quite rapidly to the end of the 1960s, 
beginning of the 1970s, they felt that they were in need of some kind of full- 
time assistance. But still pre-eminently, it was a volunteer organization and they 
could not see their way to appointing a general secretary or administrator. The 
first full-time person appointed was a social worker, Victoria Stockford, who 
operated from 1975 to 1980. It was the first sign of the introduction of 
professionalism into the society. All this is keeping pace with the development 
of medical care. Because now, towards the end of the 1960s, cryoprecipitate 
was available but not in sufficient quantities, so they began again to adopt that 
lobbying stance, pressing their centres, which were being established by then, 
pressing the Government and so on, and then all that led into the development 
of the concentrates. Again, a major lobbying function. 

In the 1970s I was invited into the presence of the Minister of State for 
Health, Dr David Owen, because one of our points for lobbying at that stage 
was the disquiet about the purity of the blood products that were coming from 
America. We had seen stories on the television of blood donors in the 



56 



Haemophilia: Recent history 

United States being recruited from Skid Row and we spoke very forcibly to 
Dr David Owen to let him know that we were not prepared to accept the risk of 
hepatitis coming from the blood products issued from the United States. All 
this was rather prophetic when you think back on those days and the ways in 
which things have changed. 

From then on, the society having got its first taste of a professional 
administrator, found it wasn't so dangerous after all: they could still not see 
their way to appointing an executive secretary or a general secretary who would 
take over the organization, they still had the thought of volunteerism in mind, 
so they appointed a coordinator, one who would not be too firm, to the point of 
excluding them from running the society, but would coordinate the efforts of 
the volunteers. The person appointed was David Watters who came into the 
office in 1981 and served with us until 1993 with great distinction. I think when 
we come to write the history of the Haemophilia Society, a very, very 
significant contribution will be shown to have been made by David Watters who 
really did introduce that note of professionalism that was required to pull the 
whole organization together. From then on, it began to be recognized by 
Government departments, by centre directors and so on, as the instrument by 
which the voice of people with haemophilia could be expressed. 

I'll go on later perhaps to say something about the way in which we have 
continued campaigning with the society, the way in which we have dealt with 
the Government in matters like HIV infection, with the supply of blood 
products and so on. But the society has also been very keen to be involved in the 
whole matter of the designation of centres, and the facilities provided by 
centres. At the same time they have had their eye not only on the people with 
haemophilia themselves, but those within the family, because there was an 
increasing concern for the sisters in the family, with the whole matter of genetic 
counselling. That has been again a very major contribution made by the society. 
Fund-raising came into it very emphatically, of course, because all this required 
money. So we've moved from those early days with a part-time secretary to 
now quite a 

substantial organization where there are specialists attached to it. There is an 
HIV worker appointed by the society and a hepatitis worker. That is the state 
where we are today. 

Lee: Can you just very briefly talk a little bit about the contribution that has 
been made towards the World Federation of Hemophilia from a British 
perspective? 



57 



Haemophilia: Recent history 

Tanner: I was thinking it's a pity Peggy Britten 167 is not with us at this 
seminar. She really is the doyenne of all supporters of the World Federation of 
Hemophilia. She was responsible for generating an immense amount of 
enthusiasm in the national society for people to play a full part in the World 
Federation of Hemophilia. The history of that is: at the first meeting in 1963 
in Copenhagen there were six national societies represented. Again, they got 
together for mutual support, they wanted to know, now that people were 
beginning to travel abroad, where they could get treatment, because what was 
available was very, very patchy in those days. They wanted to know about the 
kinds of treatment available, how to relate with the Government and how to 
develop friendships with people with haemophilia in other countries. From that 
beginning in 1963, it has now expanded to the point where practically every 
country of note has a national member organization which is represented in the 
World Federation of Hemophilia, so it's something like 88 on the present 
count. There was a particular parallel with the national society. The World 
Federation of Hemophilia started in a very amateur way, but was inspired by 
the founder, Frank Schnabel 168 who himself was a person with haemophilia and 
motivated his peers in the other national organizations. At that time, again, 
volunteerism was the key note, but now it is a highly professional organization 
which is concerned not only with sharing information but having a particular eye 
on the 

developing countries, which Peter Jones will be able to speak about. 1 9 That is 
mutual support par excellence in seeing that facilities are provided in those 
countries which are much less fortunate than ourselves in the provision of 
treatment and management. 



167 Peggy Britten (1912-1999) was unable to attend the meeting and died shortly afterwards. She 
had two brothers who died of haemophilia. Her son, Tony, also a haemophiliac, trained as a 
doctor in Johannesburg and later became Medical Director of a large transfusion centre in 
New York and Head of the Blood Programme of the League of Red Cross and Red Crescent 
Societies in Geneva. In 1965, Tony put her in touch with Katharine Dormandy to help with 
surveys into the problems of young haemophiliacs. She later became involved with the 
Haemophilia Society and World Federation of Haemophilia. She held the position of London 
Secretary and travelled extensively to many World Federation meetings. See Britten P. (n.d.) 
Living beside haemophilia in the 20th Century [unpublished manuscript] and note 170 below. 
Copies of the tapes and transcript of an interview with Peggy Britten, conducted by Professor 
Christine Lee on 19 March 1998, will be deposited with the records of this meeting in the 
Contemporary Medical Archives Centre of the library of the Wellcome Institute for the 
History of Medicine. 

168 Frank Schnabel (1926-1987), a severe haemophiliac, was a Founder of the Canadian 
Haemophilia Society and also Founder and First President of the World Federation of 
Hemophilia in 1963 when he convened the first meeting of six national societies in 
Copenhagen. 

169 Dr Peter Jones wrote: 'The World Federation of Hemophilia is a unique international 
organization, administered jointly by people with haemophilia and their relatives, and by 
doctors and scientists with an interest in the inherited bleeding disorders. Much of the present 
thrust of the their work is targeted at helping people with haemophilia in low economy 
countries.' Letter to Dr Daphne Christie, 5 July 1999. 



58 



Haemophilia: Recent history 

Lee: Yes, maybe I could mention a little bit about Peggy Britten. 
Unfortunately, she wasn't able to come today because she has got a terrible 
cold, but we are hoping to interview her subsequently. 170 She had a son with 
haemophilia who subsequently became the Head of the Transfusion Service in 
Canada and she also suffered the death of a brother with haemophilia when she 
was quite young. So she was really very involved. She worked as Katharine 
Dormandy's research assistant, to research into the educational needs of the 
children of the south of England and to that end the Haemophilia Society paid 
money for a caravan which was put on the Lawn Road site. 171 

Before we move onto what we will spend most of the rest of the time 
talking about, and that's contamination, we should hear something from Dr 
Sheila Howarth about the MRC and the provision of concentrates. 

Dr Sheila Howarth: 172 1 was very surprised that in the course of the afternoon 
credit was not given where credit was due, because much of the work that has in 
fact been described was supported by the Medical Research Council, and pretty 
lavishly considering the budget of the time. The MRC Blood Coagulation 
Research Unit in Oxford, which was directed by Gwyn Macfarlane, ran from 
1959 until Macfarlane retired in 1967, and the work was then continued under 
MRC auspices by Dr Rosemary Biggs. It trained a lot of the people who were 
seeded out throughout the country; and the Council gave fellowships for people 
to go and train there, as some people here will know. 

But to go back before that. I moved into the headquarters office of the 
MRC in 1964, and there was a haemophilia committee, the MRC Haemophilia 
Committee, chaired by Dr J F Wilkinson of Manchester, of which Professor 
Ilsley Ingram was a member and could probably tell you much more about it 
than I could. When this was disbanded in 1966, its work was taken up in the 
main by the MRC Blood Transfusion Research Committee, chaired by Pat 
Mollison, which included representatives from England and Scotland and 
directors of centres and also representatives of the services. It took haemophilia 
on board when the Wilkinson committee was wound up. It hasn't been 
mentioned that the MRC actually managed the Blood Products Laboratory for 



170 op. cit. note 167 above. See also Britten M I, Spooner R J D, Dormandy K M, Biggs R. (1966) 
The haemophilic boy in school. British Medical Journal li: 224—228. Dormandy K M, Gandy R 
H, Britten M I. (1966) Problems of management of children with coagulation disorders. 
Bibliotheca Haematologica 26: 171-175. Britten M I. (1967) Haemophilia and its problems. 
District Nursing 10: 120-122. 

171 The caravan was parked at the old Lawn Road Hospital in 1964, on the site of the present 
Royal Free Hospital in Pond Street, Hampstead. It was replaced by the purpose-built Katharine 
Dormandy Haemophilia Centre and Haemostasis Unit in 1978. 

172 Dr Sheila Howarth FRCP (b. 1920) joined the staff of the headquarters office of the 
Medical Research Council in 1964. She retired as Principal Medical Officer in 1980. 

59 



Haemophilia: Recent history 

the Department of Health, and there was a Managing Committee, which again 
was chaired by Professor Mollison. This was a difficult committee because it 
had to point out endlessly to the Health Department the increasing need for 
blood products, and that really they ought to get on with increasing the 
accommodation at Elstree 173 and with the proposed new building. The 
Department of Health almost invariably dragged its feet. They were disastrous 
meetings. Dr Dodsworth has described very politely what went on. I can 
remember one occasion when Dr Biggs and I had to take Professor Macfarlane 
as an expert witness from Park Crescent [the MRC Headquarters] , where he was 
briefed, by Tube, to a meeting at Elephant and Castle [the Department of 
Health and Social Security]. He had claustrophobia. We had the greatest 
difficulty in getting him down the escalator and onto the Tube, and having got 
him into the building at the Elephant, he stood at the bottom of the lift, dug his 
heels in and said he wasn't going to get in the lift. Anyway, we finally got him 
to the meeting, and he was our leading witness, so to speak. But the Department 
in England did drag its feet, and it was a disastrous period. 

In Scotland, they took notice of the advice which was given by the 
committees of the MRC and phase 1 of the redevelopment of the Royal 
Infirmary in Edinburgh included the fractionation laboratory, 174 so they were 
prepared when nemesis came. My information [which came from the office of 
the Haemophilia Society] was that in 1990, at the time when my haemophilic 
nephew died HIV positive in this country [England], of the 600 known 
haemophiliacs in Scotland, only 27 were known to be HIV positive, and most 
of these were suspected of having acquired the infection by association with the 
drug fraternity in Edinburgh. 175 

The other point perhaps I should pick up - I don't want to go on - is the 
Haemophilia Register. When I went to the MRC in 1964, one of the first things 
that happened to me was that two card-index files arrived on my side table, 
covered with dust, and there they continued to accumulate dust. This was called 
the Haemophilia Register and it had been set up by the MRC. People used to 
submit cards to the relevant section of the office about additional cases of 



173 See note 62 above. 

17 The Scottish National Plasma Fractionation Centre was housed in the Edinburgh Royal 
Infirmary. See Girdwood R H. (1990) Fifty years of an organized blood transfusion service in 
Scotland. Scottish Medical Journal^: 24-28. 

175 Dr Charles Rizza wrote: 'Is it being suggested that those Scottish haemophiliacs were drug 
users? Or is it being suggested that the infected drug users gave blood which infected the plasma 
supply used for fractionating factor VIII in Edinburgh? I wonder how many drug users are 
volunteer blood donors. I think the source of infection in Scotland was probably no different 
from that in England. Even if the evidence is cast-iron that drug users were the source of 
infection, I think it should be made clear that the haemophiliacs themselves were not "drug 
users".' Communication with Dr Daphne Christie, 3 July 1999. 



60 



Haemophilia: Recent history 

haemophilia as they were diagnosed. We tried to get the Health Department to 
put this on a more regular footing and we met with intense resistance. Finally 
we managed to get it handed over in 1966, when at Park Crescent [MRC 
headquarters] we had a party, as it had been such an uphill battle. I may add 
that the Register having sat on my side table, the Department then regarded it 
as something that had security risk implications, and they were said to have 
taken it down to the basement at the Elephant and Castle and locked it in the 
safe. I don't know what happened to it after that. 

Anyway, you can see that, in fact, the MRC was extremely active in this 
field, in not a passive but an active role. If we failed I think it was due to the 
fact that we could not push the Elephant [Department of Health], which has a 
period of gestation anyway of about 18 months, into any urgent action. I think 
perhaps the history of the MRC's part in this ought to be gone into in more 
detail, because it's a long time ago. I retired in 1980 and I am totally out of 
touch with what went on after that. 

Lee: Before we go to Dr Dodsworth, this Register, did it come into your 
hands, Charlie? 

Rizza: No, no. It must be locked away somewhere. 

Howarth: It's probably still locked away in the safe at the Elephant and 
Castle! 

Dodsworth: I wonder if I can make a slightly sympathetic comment with 
respect to the British Transfusion Service. The Fractionation Centre at Elstree 
never had control over its own plasma supply until the National Blood 
Authority was founded in 1993. 17 Consequently, although the facilities for 
making factor VIII were available, there was never enough plasma with which 
to make it. The situation was always somewhat easier in Scotland where the 
main concentration of population, and thus of blood donors, is close to the 
country's main transfusion centre [in Edinburgh]. When I was working in 
Manchester in the late 1960s we had no factor VIII at all and were aware that 
there seemed to be plenty in Scotland: we were very jealous. 



176 A history of blood transfusion services in the UK is given in Dodsworth H. (1996) 
op. cit. note 99 above. 

61 



Haemophilia: Recent history 

Mr ROSS Dike: 177 I would just like to make a further comment about the 
support we had from the Medical Research Council which is not often realized. 
Nearly all the advances, both in biochemical research and also in fractionation 
processes, are also consequent on the advances in the equipment that's used. In 
other words, the design and the building of novel equipment or the 
modification of commercial equipment. In this way when we moved up at the 
end of 1958 from the Radcliffe Infirmary, Oxford, into the MRC Blood 
Coagulation Research Unit at the Churchill Hospital, Oxford, we were very 
strongly supported by the MRC Central Workshops which occupied a building 
in the same hospital [the Churchill Hospital], and this led to a lot of advances, 
including such things as the successful separation of factor VIII from 
fibrinogen, 178 the equipment in which the first column fractionation of DEAE- 
cellulose factor IX was carried out, 179 etc. I could go on for half an hour 
enumerating these things. But it was in this way that part of the success of our 
research was due to the proximity of this workshop. This was proved later on 
after the retirement of Professor Macfarlane. We separated into three distinct 
units, one of them being a plasma fractionation unit, which I worked in. We d i d 
not have adequate engineering or electronic facilities after the MRC Central 
Workshop was closed, so we built and staffed our own workshops for the design, 
development, commissioning and modifying equipment and services, and the 
provision of a planned preventive maintenance programme. I think that the 
importance of this should be acknowledged. 

Bangham: I'd like to point out again that all the biological standards 
contributing to the field were made in the Division of Biological Standards at 



177 Mr G WR Dike (b. 1932) started working as Dr Bidwell's assistant in Dr Macfarlane's 
Haematology Research Unit, Radcliffe Infirmary, Oxford, in 1954 — in time to be involved in 
preparing the first dose of bovine antihaemophilic globulin which was successfully 
administered to a haemophilic patient. The Unit was taken over by the MRC (in April 1959) as 
the MRC Blood Coagulation Unit, and moved to the Churchill Hospital, Oxford, when Dike 
became an MRC Technical Officer. On Professor Macfarlane's retirement in 1967, Dike was 
involved in the planning and supervision of the subsequent building of the Plasma 
Fractionation Laboratory on the same site, and then its subsequent expansion. Dike was Safety 
Officer from 1974 and retired in 1992 as a Higher Professional and Technological officer 
(MRC) and had also been on secondment to the NHS since 1969. 

178 Bidwell E, Dike G WR Denson K WE. (1966) Experiments with factor VIII separated 
from fibrinogen by electrophoresis in free buffer film. British Journal of Haematology 12: 
583-594. 

179 Dike G W R, Bidwell E, Rizza C R (1972) The preparation and use of a new concentrate 
containing factor IX, prothrombin and factor X and of a separate concentrate containing 
factor VII. British Journal of Haematology 22: 469-490. Mr Ross Dike wrote: 'This paper has an 
illustration of the original large-scale chromatography column, and the refractometer that was 
invented and built for this work since no suitable commercial columns or in-line equipment 
were available.' Letter to Dr Daphne Christie, 22 March 1999. 



62 



Haemophilia: Recent history 

the National Institute for Medical Research until 1974. That was all work 
under the MRC. 

Douglas: Dr Howarth has mentioned the relatively low incidence of HIV 
infection amongst the Scottish haemophiliacs. One name in that connection 
should be mentioned, John Cash. 180 He was able to obtain agreement 
amongst the Scottish blood transfusion directors to favour investment in 
the plasma fractionation unit in Edinburgh and so reduced the need to use 
imported material. 

As regards the registration of haemophilia, I remember in around 1960 
filling in those green cards which Dr Howarth described earlier for issue to the 
patients and lodging the names with the MRC office in London. 

Lee: It's very interesting how Scotland is always so different. I mean the 
difference remains to the present day, when the Government gives them 
£2 million so that they can introduce recombinant factor VIII. 

I am going to change topic now and I think we need to spend some time 
hearing about the beginnings and the effects that viral contamination, and the 
side-effects of treatment, had on haemophilic patients, the people treating them 
and the whole way really we practise medicine. I think, Peter, you played quite 
a part in this in the early days. Can you start at the beginning and give us a feel 
for when the thing first began to hit. 

JoneS: I think you have to set what has happened in the context, firstly, of a 
rare disorder affecting a small number of the population of the United 
Kingdom, hence some of the resistance to the views of the MRC, the 
Haemophilia Centre directors and the patients' groups early on. You also have 
to set it against the scenario of how enthusiastic we were once effective 
treatment became available. Previously we had not been able to treat these 
little boys who were missing their schooling, had no career to look forward to, 
were growing up illiterate, were growing up crippled. We had nothing. We had 
enough factor concentrate to deal with the major surgery and that was really 
about it. Cryoprecipitate opened our eyes and then the concentrates came. We 
couldn't use the animal concentrates because they were antigenic, they stopped 
working after a while, so we turned instead to human concentrates. We knew 
from the beginning that we were transmitting disease, we knew there was 



180 Professor John Cash FRCS FRCPEd FRCPath was National Medical Director, Scottish 
National Blood Transfusion Service headquarters in Edinburgh from 1988 to 1996 and 
President of the Royal College of Physicians in Edinburgh from 1994 to 1997. 

63 



Haemophilia: Recent history 

something then called serum hepatitis, we now know it as hepatitis B, after the 
Australian antigen was discovered. 181 We knew that hepatitis B was in those 
concentrates and the companies knew that hepatitis B was in those concentrates. 
The first outbreaks of hepatitis B in the haemophilia population of the United 
Kingdom in the early 1970s were because of dumping of concentrates which 
would not have passed the Food and Drug Administration (FDA) regulations 
in the United States of America. Even that did not blunt the enthusiasm for 
treatment, because we moved on, as David Evans has said, to home therapy and 
from there to prophylaxis and to the prevention of haemophilic arthropathy. We 
also knew there was another virus in the concentrates which we then called non-A 
and non-B hepatitis and we now know as hepatitis C, 183 but all the evidence then 
from around the world then was that this too produced a chronic disorder which 
might result in ill-health in a few people. It was not thought to result in a 
devastating disease of the liver which would kill more than a few people. And 
it was worth trading that off for the improvements in haemophilia care. We 
didn't know anything about HIV, or AIDS, and this observation is important 
because in the early 1980s there was a school of thought, particularly amongst 
people who were campaigning for compensation, that we'd known about AIDS 
for years. 

It is very salutary in talking about the history of haemophilia treatment, 
and the history of medicine in general, to realize that advances in care are rarely 
straightforward. There's a cartoon by Matt on the front of the Daily Telegraph 
today and I paraphrase it, 'We have known about spongiform encephalopathy for 
a long time, but it has taken us two years to know how to pronounce it.' In the 
early 1980s there was this feeling that we had all known that there was another 
virus there, and if we look at some of the features at the beginning of the HIV 
epidemic and what we now know about new variant CJD (nvCJD), it's a little 
chilling. First of all the timing. In every decade of modern haemophilia 
therapy a new virus has appeared. We have been through the hepatitis alphabet of 
A, B, C, delta, E, and we are down to G. We have found parvovirus. Every 
decade brings a new virus: so HIV in the early 1980s, 185 then hepatitis C 



181 Baruch Samuel Blumberg won the Nobel Prize in 1976, jointly with D Carleton Gajudsek, 
for his discovery of the Australian antigen associated with hepatitis B virus. See Blumberg B S. 
(1984) The Australian antigen story. In Millman I, Eisenstein T, Blumberg B S. (eds) Hepatitis 
B: The virus, the disease, and the vaccine. New York: Plenum Press, 5-31. 

182 The Food and Drug Administration (FDA) of the USA (founded in 1938) is the premier 
drug regulatory organization in the world, inspecting and licensing the manufacture of foods, 
cosmetics, pesticides as well as human and veterinary medicines. 

183 See note 92 above. 

18 op. cit. note 88 above. 
185 op. cit. note 87 above. 



64 



Haemophilia: Recent history 

recognition in the early 1990s, 186 and now a question mark. Initially, HIV and 
now nvCJD had well-defined patient groups; with CJD we have the growth 
hormone group. 1 7 Animal connections are obvious with nvCJD, the green 
monkey with HIV. With CJD we don't know where the infection is, there isn't 
a test; the same for HIV was true. Query - is it transmissible by blood? 

With HIV, we realized that we had got a problem after the description of 
the first cases in 1981. The Haemophilia Centre directors thought very long and 
hard, and thought that one in a thousand people who had been transfused with 
contaminated products would develop AIDS. One in a thousand. Again it was 
something to be concerned about, but perhaps to put on one side in favour of 
continuing treatment. We didn't know any means of removal. Heat treatment 
had been tested to try to get rid of hepatitis viruses, but in fact if it had been 
tested heavily in the 1970s it probably would have been rejected and not 
thought of for HIV, because it did not stop transmission of hepatitis. With 
CJD, as was the case initially with HIV, there's no individual donor testing. 
There's no surrogate testing. There's a very long incubation period which is 
what caught us out with 'the one in a thousand' at the beginning of HIV. CJD is 
a deadly disease, there is no known treatment. Now with HIV we've moved on 
and we have got long-term survivors. Both CJD and HIV have produced terrific 
dilemmas for the authorities. You have only got to think of beef on the bone, 
and the scepticism of the public. It's a catch-22 situation, 188 there is enormous 
publicity, much of it ill-informed. The media like to think in terms of black 
and white, there is no grey area in the middle. When doctors say they don't 
know, or scientists say they don't know, it adds to the uncertainty. So there is a 
tendency for the Government, and we have already heard the MRC perspective 
about transfusion, 189 to follow a course of action without telling those at the 
leading edge. That was certainly true at the beginning of HIV and may now be 
true in the case of CJD in the case of the farmers. At the beginning of the HIV 
epidemic I thought that it must have been almost like being in World War I 
when the generals were doing one thing and the men were all doing something 
else. I felt very much like the brigadier in Dr Who because I felt that I had to 
be pragmatic and act, but there was nobody to turn to; there was no leadership 
whatsoever from central Government or the Department of Health. In fact, if 



186 See note 92 above. 

187 Knight R, Stewart G. (1998) The new variant form of Creutzfeldt-Jakob disease. FEMS 
Immunology and Medical Microbiology 21: 97-100. See also Lee C A (1996) Transfusion- 
transmitted disease. Baillieres Clinical Haematology 9: 369-394. 

188 Catch-22 - A no-win situation. 'Orr would be crazy to fly more missions and sane if he 
didn't, but if he was sane he had to fly them. If he flew them he was crazy and didn't have to; but 
if he didn't want to he was sane and had to.' Heller J. (1961) Catch-22, Ch. 5. Leicester: 
Charnwood. 

189 See discussion on page 59. 

65 



Haemophilia: Recent history 

anything, in the initial years there was antagonism. There was an enormous 
amount of money spent fannying around, when all that was really needed was to 
put every Haemophilia Centre director and the small number of other people 
working with the early groups affected by HIV, particularly in London and 
Edinburgh, onto a jumbo jet and take them to the United States to teach them 
how to look after people with AIDS and prevent transmission. 19 ° 

Then followed, of course, the discovery that the majority of our severe 
haemophilic patients were affected, and I wish the story that you gave us about 
Scotland was true, but it isn't; there were many more patients in Scotland 
infected and infected with Scottish product. 191 Then there followed a campaign 
for 'recompense', we called it, because 'compensation' suggested no-fault 
compensation and Government blocked that, of course, for people with 
haemophilia and their families and the survivors. 192 And that led to the 
Macfarlane Trust with the first £10 million which came from Mrs Thatcher. 
One afternoon at three o'clock she suddenly said, 'We'll do it, there's the 
money'. Why she did it, we have never discovered. 

Lee: Didn't that happen when John Major came in? 

JoneS: No. The first £10 million for the Macfarlane Trust came from 
Margaret Thatcher. The later payments, two extra payments to people with 
haemophilia, were from John Major's Government and that came after 
prolonged litigation which was very, very uncomfortable. In medical practice 
when you are being litigated against, normally the patient isn't your own 
patient. You can push the patient, if that is the right way of putting it, onto a 
colleague. But in this case, you couldn't. So we had Haemophilia Centre 
directors looking after patients and families, and at the same time being 



190 Dr Peter Jones wrote: 'It should be remembered that the haemophilic population was hit by 
HIV first, about two years before the epidemic became apparent in the general population, 
because of the direct inoculation of the virus in treatment. So the directors were at the leading 
edge of the epidemic in this country.' Letter to Dr Daphne Christie, 5 July 1999. 

191 See Simmonds P, Beatson D, Cuthbert R J, Watson H, Reynolds B, Peutherer J F, Parry J V, 
Ludlam C A, Steel C M. (1991) Determinants of HIV disease progression: six-year 
longitudinal study in the Edinburgh haemophilia cohort. Lancet 338: 1159—1163. 

192 The term 'recompense' was used because the Government would not support no-fault 
compensation. Dr Peter Jones wrote: 'The initial campaign in 1987 was orchestrated 
principally by David Watters [see page 57] and his colleagues in the Haemophilia Society and 
Dr Jones in Newcastle. Intense lobbying of Parliament was undertaken and included the 
distribution of a booklet, This is URGENT. Haemophilia and AIDS, which detailed the 
hardship being experienced by people with haemophilia and their families, to members of 
both Houses and to the media.' Letter to Dr Daphne Christie, 5 luly 1999. See Jones P. (1987) 
Hidden victims of AIDS. 
The Times (9 October 1987). idem Haemophilia, AIDS, and no fault compensation. 
British Medical Journal '295: 944-945. 



66 



Haemophilia: Recent history 

litigated against for HIV infection and subsequently AIDS, and that took 
personally two years out of my clinical life. I had to shut my door and just go 
through all the records for litigation. Some of my personal record of the time 
has already been published. 193 That still continues with hepatitis C of course. 
God willing, we are not going to see CJD as a transmittable disease to the 
haemophilia population. Hopefully it will not be long before we know the risk 
factors, because the risk committee and SEAC, the Spongiform 
Encephalopathy Advisory Group, reports to ministers in March, so we may have 
a better idea then. 1 As Alan [Tanner] said, the Haemophilia Society has 
grown into a very well-presented professional lobbying body, but in some cases, 
and in the case of the World Federation as well, it has left in its wake 
difficulties, some bitterness, some doctors who don't want to know anything 
about haemophilia ever again, and this continues even today with HIV. Thirty 
of our colleagues in France have been charged officially with poisoning and 
stand trial to spend the rest of their lives in prison. 195 These are colleagues just 
like people sitting in this room, who I know perfectly well behaved just as we 
did at that time. 

Lee: One is a Professor of Transfusion Medicine in this country. 

JoneS: I see Jean-Pierre Allain 196 was invited to the meeting and couldn't 
come. He has already been in prison for his role in the French HIV epidemic 
and, in Japan, colleagues have also been put in prison for their involvement with 
HIV and still problems exist. So young physicians, young haematologists, are 
reluctant to treat people with haemophilia because they are frightened that they 
will be embroiled in litigation and difficulties in their professional lives. So 
the sadness of HIV from the professional point of view is still with us, and I 



193 Berridge V. (1996) op. cit. note 90 above, for example pages 38-40, 62. 

19 Dr David Tyrrell wrote: '...There was the opinion from SEAC [Spongiform 
Encephalopathy Advisory Committee, also known after its Chairman as the Tyrrell 
Committee, see note 203 below] that there was a theoretical risk of new variant CJD from 
blood. They made recommendations on sourcing and processing of blood products'. Letter to 
Dr Daphne Christie, 13 March 1999. See a summary of the meeting held on 9 March 1998, in 
MAFF News 119/98, 25 March 1998. 

195 Butler D. (1994) Mitterrand asked to pardon doctors in HIV blood scandal. Nature 367: 206. 
Anonymous. Contaminated blood continues to boil. ibid. 301. 

196 Professor Jean-Pierre Allain, Professor of Transfusion Medicine in Cambridge, and 
Director of the East Anglian Blood Transfusion Service, was sentenced by the French Courts to 
a term of imprisonment when he was working in Paris in 1984—1985. His alleged crime was to 
have done too little to prevent the transmission of HIV to haemophiliacs. See Carrell R W, 
Peters K, Cash J, Mollison P L (and 33 others). (1993) Imprisonment of J-P Allain. Lancet 343: 
244. Lachmann P J, Bellingham A J, Banatvala J, Carrell R, Hoffbrand V, Wagstaff W. (1993) 
Statement of the Royal College of Pathologists on the matter of Professor Jean-Pierre Allain: 
19 November 1993. The Bulletin of the Royal College of Pathologists: 84: 3-4. 

67 



Haemophilia: Recent history 

don't really need to say what sadness there has been in the patient population, 
because it has been dreadful. We have seen three generations now of patients 
affected and in the face of all this our Government, both the Conservatives and 
the Labour Party, have refused to endorse the unanimous opinion of the 
Haemophilia Centre directors that recombinant factor VIII and now factor IX 
is probably safer than the plasma products and therefore must be the treatment 
of choice for people with 

severe haemophilia. 

Lee: Thank you, Peter. Before we move onto recombinant [factor VIII and 
factor IX] for the last part of this there are two things I would just like to 
encourage along the way. This is a horrific story but alongside that horrific 
story is a good story, in that the life expectancy for somebody with 
haemophilia in the late 1930s was 20 years. And this came up very strongly in 
the conversation we had with Dr Biggs. We were talking about the school at 
Treloar 197 and I said I had a number of adult patients who were at Alton, and 
sadly they were ones who had died of AIDS, who'd known each other when they 
were all boys together at Alton. She responded by saying, 'Of course, the next 
thing that started to crop up was they started to get jaundice'. Dr Biggs 
published on jaundice in 1974 198 and, I think, was probably the first person who 
actually put into print this complication. And she said, And what we felt at the 
time was that they were better alive and having jaundice, than dead with 
haemophilia'. 199 1 think that it is important that although this terrible thing has 
happened, alongside it has developed good treatment and we'll hear a bit more 
about that in a minute from Ted [Tuddenham] . 

Charlie [Rizza], before we leave HIV, I hesitate to say this, but from the 
haemophilic patients who'd been infected, a lot of science has come which has 
actually helped our understanding of the natural history and the biology of 
HIV. Would you like to talk a little bit about those data and how they've been 
published, and collated, and helped our understanding. 



197 The Lord Mayor Treloar Hospital and College at Alton accepted pupils with crippling 
diseases and nearly a third of the boys at the college were haemophiliacs. See Gaumont British 
Instructional (1945) A Job Well Done (Lord Treloar Hospital and College in Alton, Hants). 
Videocassette copy, 1989, Handlist number 183, Wellcome Trust Video Library. See also 
Britten M I, Spooner R J D, Dormandy K M, Biggs R. (1966), op. cit. note 170 above. 

198 Biggs R. (1974) Jaundice and antibodies directed against factors VIII and IX in patients 
treated for haemophilia or Christmas disease in the United Kingdom. British Journal of 
Haematology 26: 313-329. 

199 op. cit. note 2 above, 772. 



68 



Haemophilia: Recent history 

Rizza: This stems largely from the organization of care, the registration of 
information, the gathering of data. We were in a very strong position in this 
country, compared with other countries, in that we had a very good database to 
start with. Very easily we picked up information on the prevalence and 
consequences of HIV, and along with the people working with Sir Richard 
Doll worked on the long-term effects, and the effects of age for instance at 
the time of infection. But we also managed to scupper the story which was being 
put about by some very serious people in the United States, that HIV had 
nothing to do with AIDS and it was a 'bystander effect' 201 and it was this thing 
called 'lifestyle' which caused AIDS. No-one could explain to me what the 
lifestyle was of the wife of a haemophiliac who had got AIDS or the lifestyle 
of a newborn babe who had got it from his mother, the wife of a haemophiliac. 
So the data we collected was valuable in that respect and probably put an end to 
that story. 202 It hasn't surfaced again. It tends to come up when Professor 
Duesberg is asked to speak. It's my own personal view that medicine seems to 
stumble from one disaster to the next. All the way through it has been like that. 
You develop what you think is good therapy and you find that a significant 
number of patients suffer as a consequence, but at the end of it there's been a 
little bit of advance. It is a shame that people have to suffer to get there and this 
is my own personal feeling, others may not think that. All new therapies are 
potentially dangerous, I think, and have to be used with great care. 

Lee: One of the really good things that came out of HIV was a real push to get 
a safe product and I suppose in the beginning it was sterilization, but then there 
was the push to move to recombinant. 



200 Professor Sir Richard Doll Kt CH OBE FRCP FRS (b. 1912) was Regius Professor of 
Medicine at the University of Oxford from 1969 to 1979, now Professor Emeritus. He was 
Chairman of the Adverse Reaction Sub-Committee, Committee on Safety of Medicines, from 
1970 to 1977 and has been Honorary Consultant, Imperial Cancer Research Fund Cancer 
Studies Unit, Radcliffe Infirmary, Oxford, since 1983. See Darby S C, Rizza C R, Doll R, 
Spooner R J, Stratton I M, Thakrar B. (1989) Incidence of AIDS and excess mortality associated 
with HIV in haemophiliacs in the United Kingdom: report on behalf of the directors of 
haemophilia centres in the United Kingdom. British Medical Journal 298: 1064-1068. Darby S 
C, Doll R, Thakrar B, Rizza C R, Cox D R. (1990) Time from infection with HIV to onset of 
AIDS in patients with haemophilia in the UK. Statistics in Medicine 9: 681-689. 

201 Professor Peter Duesberg, a Californian molecular biologist, claimed no connection 
between HIV and AIDS. See for example Duesberg P. (1988) HIV is not the cause of AIDS. 
Science 241: 514, 417. idem (1994) Infectious AIDS - stretching the germ theory beyond its 
limits. International Archives of Allergy and Immunology 103: 118-127. See also Berridge V 
(1996) 'Orthodoxy and fringe': the anti-AIDS alliance, op. cit. note 90 above, 231-251. 

202 See Darby S C, Ewart D W, Giangrande P L F, Dolin P J, Spooner J D, Rizza C R (1995) 
Mortality before and after HIV infection in the complete UK population of haemophiliacs. 
Nature 377: 79-82. 



69 



Haemophilia: Recent history 

Rizza: Don't let us assume that recombinant is perfectly safe. That is the next 
step. You mustn't assume that. That will take 20 years of work, or ten years to 
see the fallout. I hope it is perfectly safe, but you can't assume that. 

Dr David Tyrrell: 203 I would like to mention one other group who were 
involved, a group with whom I sat, namely the Biological Products 
Subcommittee of the Committee on Safety of Medicines and its 
predecessors. I always felt we were sitting in a rather hot seat in respect of the 
successive applications which various manufacturers made for products derived 
from blood. I think it is important to realize that from the very beginning 
people knew that they were dealing with a gamble. Blood transfusion began as 
we have heard in the 1930s and 1940s and that revealed the presence of hepatitis 
viruses in blood. We knew also that although you could do some biochemistry, 
there was no way of ensuring that they wouldn't be there in the product. 
Therefore there is an aphorism used by people in this area, saying that the one 
way of making a non-infectious product is to start with something that is non- 
infectious. So, if you want to make a product that you are sure is non-infectious 
the only place you know that you can find your product is in blood, that means 
you don't make the product! As we were aware of this, it was part of the 
documentation that every ampoule should have a warning that there was a risk of 
infection. It was up to us to evaluate how the product had been made (which 
would include its source, its processing and so on), and the physician who used 
it to decide whether there was more benefit to the patient to have this product 
or not to have it and receive some other form of management. The succession of 
catastrophes as you described them parallel the series of advances in virology. 
Once, as you said, we were worried about hepatitis B, but after some very hard 
and very good work a way of testing for hepatitis B was discovered, 205 so it was 
removed from the initial starting material. The same thing happened over 
hepatitis A, then it happened over hepatitis non-A, non-B, now called hepatitis 
C. I am recalling this because people have said that the manufacturers didn't 
care. I have heard this said in emotional broadcasts, 'They didn't bother about 
the fact that they might kill my child or whoever'. I think it is important to 



203 Dr David Tyrrell CBE FRCP FRCPath FRS (b. 1925) was a member of the scientific staff 
of the MRC Common Cold Unit at Salisbury from 1957 and its Director from 1982 until his 
retirement in 1990. He was Chairman of the Spongiform Encephalopathy Advisory Committee 
(SEAC), from February 1989 until 1995. 

204 The Committee on Safety of Medicines (CSM) was created by the Medicines Act 1968 with 
similar functions to the preceding Committee on Safety of Drugs, which operated from 
January 1964 to September 1971, when the new Committee started. Along with the Committee 
on Veterinary Products, it advises the Licensing Authority. See Tansey E M, Reynolds L A (eds) 
(1997) The Committee on Safety of Drugs. In Wellcome Witnesses to Twentieth Century 
Medicine, vol. 1. London: The Wellcome Trust, 103-135. 

205 op. cit. note 181 above. 

70 



Haemophilia: Recent history 

sometimes try and see it as a necessary corollary of the way science actually 
works. As somebody said we actually do not go forward like a Horizon 
programme suggests, with a hypothesis that is followed by a neat series of 
experiments all of which build up to a tidy conclusion. We stumble forward, 
and this is part of the stumbling; in the stumbling process we can do good on 
the way and it's a matter of the art of medicine (which hasn't gone away I am 
sure) to try and do the good and minimize the harm. But the aphorism which I 
mentioned before still applies and supports what you have just said about 
recombinant products. We know we can make recombinants in a bottle or a tube 
which doesn't contain an infectious virus and if you want a non-infectious 
product in the end, that must be a better place to start than one which is bound 
to contain at some stage some infectivity. 

Dr Angela Dike: 206 I worked at the Oxford Blood Transfusion Centre for the 
last 19 years and what I wanted to say complements the previous speaker. I 
would like to fill in a gap between the discovery of viruses in blood, and the 
leap to the demand for recombinant plasma products. During this interval the 
National Blood Transfusion Service made rapid progress towards improving 
the safety of blood transfusion, by introducing a succession of increasingly 
sensitive laboratory tests for the presence of hepatitis viruses and HIV in 
individual blood donations, and by progressing towards very searching 
questioning of would-be blood donors so as to exclude any with obvious 
infection risks, so that blood transfusion now is considerably safer than it was in 
the 1970s. 207 

JoneS: I think that the last two speakers are obviously absolutely right and 
perhaps it's what Christine said before: that haemophilia and what has happened 
to people with haemophilia as a result of a viral infection has been a spur to a 
lot of science. It was probably individual donor testing that made blood safer 
rather than any of the early anti-HIV tests and the treatment of the blood 
products themselves. I take what you [Tyrrell] are saying about the Committee 
on Safety of Medicines, 208 but still blood products in this country that are 



206 Dr Angela Dike FRCPath (b. 1936) joined the Oxford Haemophilia Centre in 1966 as a 
medical registrar, when Rosemary Biggs and Gwyn Macfarlane were still working there, and 
where she met Ross (see note 177 above), her husband. She became an Associate Specialist at the 
Oxford Blood Transfusion Centre from 1977 to 1996 and is now retired. 

207 Dr Angela Dike wrote: 'The risk of transmitting hepatitis B, hepatitis C or HIV in an 
individual blood donation is now of the order 1 in 500 000. If plasma products were now 
made from small pools they would, of course, be much safer than the products 
being made nowadays from pools of 5000 or more individual blood donations.' Letter to 
Dr Daphne Christie, 4 July 1998. 

208 op. cit. note 204 above. 

71 



Haemophilia: Recent history 

imported are not labelled with their country of origin. When I buy fishfingers 
from Sainsbury's, I know where they have come from, and I know where my 
honey comes from, but I don't know where blood products come from. I also 
know that as well as hepatitis B, manufacturers knowingly imported blood 
products which were known to be HIV positive. I also know that within the 
European Community, and I have documentary evidence, there has been re- 
labelling of blood products, unknown to the Committee on Safety of 
Medicines. These things go on whenever you've got a product which is being 
sold for profit and they are bound to happen, we have to say that they happen, 
and it's our duty to try to stop them happening. We are involved with this very 
much in the World Federation of Hemophilia in the developing world with the 
companies at this moment, because we rely on the companies for the treatment 
of haemophilia. We have to work with them and the best way of working with 
them is to be open and honest and work towards a safe product. So I take 
everything you say from the Committee on Safety of Medicines, but the 
background of it is again what I refer to as secrecy. It's the difficulty of being 
at the sharp end and facing a family and somebody with haemophilia with the 
knowledge that things have gone wrong in the past, and not being completely up 
to date with the Committee on Safety of Medicines, perhaps for very 
legitimate reasons, for commercial secrecy reasons at the same time. 

Lee: We can't leave this room tonight without discussing the history of 
recombinant and I am looking at Professor Tuddenham who, as many people 
will know, was involved in the purification of factor VIII that made this 
possible. Ted could you just give us a little bit of the insight. Why did you 
start purifying factor VIII? 

Tuddenham: I began my career in pathology in 1969 in Liverpool where I 
was an SHO [senior house officer] on a pathology rotation. One of the duties 
was to treat the haemophiliacs under David Weatherall's 209 care. This involved 
going down to what was called the tropical ward then, which was part of that 
wonderful Victorian building that's now all boarded up in central Liverpool, 
and filling out bag, after bag, after bag of cryoprecipitate, drawing it up in 
syringes and injecting it very slowly and I found this a terribly primitive, 



209 Professor Sir David Weatherall Kt FRCP FRCPath FRS is Regius Professor of Medicine 
at the University of Oxford, since 1992, Honorary Director of the MRC Molecular 
Haematology Unit, since 1980 and a Wellcome Trust Governor since 1990. He was Nuffield 
Professor of Clinical Medicine at the University of Oxford from 1974 to 1992 and Fellow of 
Magdalen College, Oxford, from 1974 to 1992, Emeritus Professor since 1992. He has been 
President of the British Society for Haematology since 1980 and the International Society of 
Haematology, since 1992. 



72 



Haemophilia: Recent history 

intriguing process. I started talking to haemophiliacs. We had one patient who 
didn't respond at all and I went along to the lab and tried to sort it out with 
Alan Smith, the technician, and we came to the conclusion that there had to be 
an inhibitor, so it sort of sparked off my interest in haemophilia. Then I got a 
job in Cardiff with Arthur Bloom 210 and that really was what got me launched 
on the serious study of blood coagulation. That was 1971. At that time there 
were a lot of confusing ideas around as to the nature of haemophilia and von 
Willebrand's disease, recognized as a separate and distinct genetic entity, and 
there were rival theories which were really quite hotly contested in the 
literature. One idea was that there was just one molecule of factor VIII 
which was also deficient in von Willebrand's disease, and a biochemist called 
McKee in the States refused to be convinced that you could in any way separate 
the von Willebrand property, the platelet adhesion-promoting property, from 
the coagulation-promoting property. At one point if you said that they were in 
any way separable you couldn't actually get the thing published in either the 
Journal of Biological Chemistry or the Journal of Clinical Investigation which I 
presumed was because he was a reviewer. A great advance, as has already been 
mentioned, was made in 1971 by Zimmerman, Ratnoff (the other proposer of a 
cascade hypothesis) and Powell who had raised an antibody that detected a line 
in the plasma of severe haemophiliacs, but no line 212 in the plasma of a severe 
von Willebrand's disease patient, which they called factor VHI-related 
antigen. 213 There were various names floating around for this, including 
antihaemophilic factor antigen, while the coagulation-promoting activity was 
also called various things. 

When I arrived in Cardiff, Arthur Bloom had just started putting together 
all these differing and confusing biochemical, immunological and genetic 
results. He called us into his office one morning in 1972 to give us the benefit of 
his way of explaining all of this. He said there had to be a high molecular 
weight protein that's deficient in the von Willebrand's disease and a low 



210 Professor Arthur L Bloom (1930-1992) was one of the first to establish factor VIII and von 
Willebrand's factor as separate molecular entities. He was awarded a Personal Chair in 
Haematology in Cardiff in 1976 and was a past President of the British Society of 
Haematology and of the British and International Societies of Haemostasis and Thrombosis. 
He was Chairman of the United Kingdom Haemophilia Centre Directors Organization from 
1979 to 1985. 

211 For example McKee maintained that the two activities - antihaemophilic and platelet 
adhesive - are properties of one molecule. McKee P A (1981) Observations on structure 
function relationships of human antihemophilic/von Willebrand factor protein. Annals of the 
New York Academy of Sciences 370: 210-226. 

212 See note 12 above. 

213 Zimmerman T S, Ratnoff O D, Powell A E. (1971) Immunologic differentiation of classic 
hemophilia (factor VIII deficiency) and von Willebrand's disease. Journal of Clinical 
Investigation 50: 244-254. Kernoff P B, Rizza C R. (1973) Factor- VHI-related antigen in 
female haemophilia. lancet 'u: 734. 

73 



Haemophilia: Recent history 

molecular weight protein deficient in haemophilia A that's coded on the X 
chromosome. They are associated together in plasma and you can separate 
them, as had been shown earlier by Owen and Wagner. 214 A high molecular 
weight protein would be involved in platelet adhesion, but also in supporting 
factor VIII in the circulation. This was to explain why, if you infused plasma 
or factor VIII concentrate into a patient with von Willebrand's disease there 
appeared in the circulation more factor VIII activity than you had infused in 
the first place. 

The other thing he did that got me absolutely hooked on biochemical 
coagulation, was he paid for me to go to a meeting of the International Society 
of Thrombosis and Haemostasis in Vienna in 1973. At that meeting Stephan 
Magnusson announced the complete primary amino-acid sequence of bovine 
prothrombin. 215 I thought, 'Right, I want to get the complete amino-acid 
sequence of factor VIII'. It took another 12 years, but that is what originally 
inspired me. I also had the privilege of having a waltz in Vienna with Katharine 
Dormandy, who became significant later in my life. I also bumped into 
Rosemary Biggs in the street when I'd got lost and asked her the way to the 
conference centre and she gave me directions. As far as I can remember that was 
the first and last time that I had any kind of interaction, social or scientific, 
with the research group in Oxford. 

In 1976 I had the opportunity to go to the States after I had completed 
my training, got the various bits of paper, and Arthur Bloom got me a job with 
Leon Hoyer who was the other most prominent researcher on factor VIII at that 
time. He had started on separating factor VIII from von Willebrand's factor 
and I spent two very happy years there. We had an antibody to the von 
Willebrand's factor, which enabled us to grab the whole complex out of 
plasma, and then we could elute factor VIII with, as it happened, 0.24 M 
calcium chloride, which was free of von Willebrand's factor, and we were able 
to start doing some biochemical studies on that. We published that data, 217 then 



214 See for example Hurt J P, Wagner R H, Brinkhous K M. (1966) Human antihaemophilic 
factor (AHF) purification: a comparison of two procedures. Thrombosis et Diathesis 
Haemorrhagica 15: 327-337. Wagner R H. (1968) Recommendations of the subcommittee on 
human factor VIII (AHF) and factor IX (PTC) preparations, ibid. 35: 235-237. 

21> Magnusson S, Sottrup-Jensen L, Claeys H, Zajel M, Patersen T E. (1975) Complete primary 
structure of prothrombin. Partial primary structures of plasminogen and hirudin. Thrombosis 
et Diathesis Haemorrhagica 34: 562-563. 

216 See for example Hoyer L W, DeLos Santos F R P and Hoyer J R. (1973) Antihemophilic 
factor antigen - localization in endothelial cells by immunofluorescent microscopy. Journal 
of Clinical Investigation 52: 2737-2744. Hoyer L W. (1975) Factor VIII subunits. Annals of the 
New York Academy of Sciences 240: 84-94. 

217 Tuddenham E G, Trabold N C, Collins J A, Hoyer L W. (1979) The properties of factor 
VIII coagulant activity proposed by immunoadsorbant chromatography. Journal of Laboratory 
and Clinical Medicine 93: 40-53. 



74 



Haemophilia: Recent history 

I came back to the Royal Free and set up a small lab to start trying to do this 
on a larger scale. We did have support from the MRC towards developing 
monoclonal antibodies and these were absolutely key. Over the next three years, 
especially with the help of Alison Goodall, we got monoclonal antibodies to 
factor IX which were the first monoclonals to a clotting factor, to factor VII 
and to factor VIII, and I remember talking to the head of the transfusion 
service at Elstree during that period, suggesting to him that the future of high 
purity for blood coagulation factors would be monoclonal purification. For 
various reasons, which we haven't got time to go into, they didn't get taken up 
by the transfusion service here. It is now, of course, used by all commercial 
laboratory concerns for high-purity fractionation. 

In our efforts to purify factor VIII we worked with Speywood; David 
Heath ran Speywood in Wrexham and he'd been developing a method of 
making pig factor VIII which would be free of the platelet-clumping activity 
which Charles Rizza referred to earlier, and I was very interested in his story of 
patients seeing stars. When you purify pig factor VIII you also get pig von 
Willebrand's factor and that directly aggregates human platelets, so to get a 
good product, you need to get rid of that. Something that Alan Johnson, 219 who 
was also mentioned earlier, had developed was a process for purifying factor 
VIII, human factor VIII he was working with, which would get rid of the von 
Willebrand's factor and give you mainly factor VIII. The problem with 
dissolving the early concentrates was that they were actually a heavy cake of 
fibrinogen and fibronectin with an extremely light contamination of factor 
VIII, more or less just sort of a little bit of a dirty scum on the main cake of 
stuff. So getting rid of all that was very important. We formed a collaboration 
with Speywood to have a major go at purifying factor VIII, which we achieved 
by 1982, and went to a congress in San Diego where we announced that. We 
got talking to Genentech Inc. and as they say the rest is history; we purified 
about 20 milligrams of factor VIII from about 2000 litres of human blood, 
and that was sequenced and enabled the cloning and expression of recombinant 
factor VIII. Over this period I have always felt that what we should be aiming 



218 Speywood Laboratories (Wrexham, UK) prepared a highly purified antigen using Maws 
porcine factor VIII material. See note 53 above. 

219 See note 35 above. 

220 Tuddenham E G, Lane R S, Rotblat F, Johnson A J, Snape T J, Middleton S, Kernoff P B. 
(1982) Response to infusions of polyelectrolyte fractionated human factor VIII concentrate in 
human haemophilia A and von Willebrand's disease. British Journal of Haematology 52: 
259-267. 

221 These conference proceedings were not published. Results were published later in 1985, see 
Rotblat F, O'Brien D P, O'Brien F J, Goodall A H, Tuddenham E G D. (1985) Purification 
of human factor VIIIx and its characterisation by Western blotting using monoclonal 
antibodies. Biochemistry 24: 4294-4300. 

75 



Haemophilia: Recent history 

at is the highest level of biochemical purification, first to produce high-level 
purity concentrates that are free not just of viruses but of the other unwanted 
side-effects of infusing very impure concentrates. Secondly, to lead into the era 
of molecular biology, because the purpose of sequencing factor VIII was to 
enable its cloning by the classical biochemical route and to enable synthesis. 

I heard Charles Rizza mention that it has yet to be proved that the 
recombinant material is completely safe and, of course, I would agree with 
that. Everything that we give to a patient has to be subjected to the most intense 
scrutiny and I think I would say, and others might agree, that the trials of the 
recombinant material have been more intensively scrutinized and more 
extensively followed than the introduction of any other blood products have 
been in the past. Of course, we have had the benefit of hindsight, learning from 
the problems of introducing other concentrates that weren't sufficiently closely 
followed at the time. Up to this point, I am not aware of any serious or indeed 
any complication of using recombinant material for treating haemophiliacs, 
other than the development of inhibitor antibodies, 222 another large issue we 
don't have time to go into, but up to this point they appear to have a perfect 
safety record. The only down side that I can see is that we are still using 
plasma-derived albumin as the protein for the carrier for these concentrates, the 
recombinant concentrates, but shortly that will surely be replaced with 
recombinant albumin. 

Lee: It's interesting that the first patient in the UK who had recombinant, I 
think, was in 1988. We at the Royal Free continued treating a second patient 
until 1994 when it was licensed. Promptly when it became licensed that patient 
had to be treated with plasma-derived concentrate, because it was too expensive 
to continue giving him the recombinant. It's with that really in mind that I 
thought we should end with a note of where we are at now. Peter Jones alluded 
to the fact that the UK Haemophilia Centre directors have guidelines 223 which 
recommend that patients should be treated with recombinant factor VIII which 
is licensed now, and recombinant factor IX when it becomes licensed and we 
are reasonable people and we realize that there isn't a bottomless pit, so we've 
suggested that children should be the priority. In this country, I think there are 
about 600 children with severe haemophilia A and half of them are being 



222 Nilsson I M, Berntorp E, Zettervall O. (1988) Induction of immune tolerance in patients 
with hemophilia and antibodies to factor VIII by combined treatment with intravenous IgG, 
cyclophosphamide and factor VIII. New England Journal of Medicine 318: 947-950. Hoyer L W. 
(1995) Factor VIII inhibitors. Current Opinion in Hematology!: 365-371. 

223 United Kingdom Haemophilia Centre Directors Organization Executive Committee. 
(1997) Guidelines on therapeutic products to treat haemophilia and other hereditary 
coagulation disorders. Haemophilia?): 63—77. 



76 



Haemophilia: Recent history 

treated with recombinant as of now, and the other half aren't for reasons of 
economics. I thought it would be helpful to really tie up the issues of cost and I 
want to refer again to Dr Biggs's interview. 224 She talked about the factor VIII, 
this was in the 1970s, being on the pharmacy budget and she said, 'Yes it was, 
we used more than half the area's money for medicine, just on haemophilic 
patients'. At the Royal Free we spend £10 million a year on haemophilia and I 
think the total hospital budget is £124 million pounds, so it's a tenth of the 
hospital's budget. 

Before I hand over to Clifford [Welch] to talk about this issue, I think we 
have to remind Ted that some of his research, since we are in the business of 
reminding who's helped in this business, was actually funded by The Katharine 
Dormandy Trust. 225 

In the summer, Clifford, who doesn't mind me sharing with you that he has 
mild haemophilia, had a terrible bout of cholecystitis. He was pretty close to 
going, and he had his gall bladder removed using continuous infusion of 
recombinant factor VIII, so I think he understands where we have been and 
where we have arrived at, and he certainly understands the problems of the 
economics of delivering this care in 1998. 

Welch: I'll be very, very brief because time is getting on, but to me the last 
65, 70 years, have been quite extraordinary. I trained as a scientist and 
therefore, although I have no special knowledge of medicine, I do have some 
knowledge of research. To see what an extraordinary transformation has 
occurred from the time when I remember going, as I mentioned earlier, to 
Bart's with one of my brothers and my mother, to today. This boy was 
practically at death's door, and I vividly recall the expression on the faces of 
the house surgeon and physicians who were trying to deal with a situation totally 
outside their experience. They didn't know what to do. Today we have these 
extraordinary developments. Despite the scourge of HIV and hepatitis C, the 
fact is that we can now expect to live normal lives as haemophiliacs, to grow up, 
to have children, and to see our children 

grow up as normal children too and 30, 40, 50 years ago that was certainly not 
the case. 

As a result of all that Katharine Dormandy achieved, she, like Gwyn 
Macfarlane, had a profound influence upon my life and enthused me 
enormously, by virtue of the unwavering dedication she gave to her patients. I 



op. at. note . 

22 Dr Katharine Dormandy, Director of the Centre for Haemophilia and Haemostasis, set up 
the Trust Fund in 1971; see biographical note 111 above. 



77 



Haemophilia: Recent history 

felt that one had got to try to put something back. And one of the things that we 
have been trying to do with Katharine Dormandy's Trust down the years is to 
make sure that her objective of searching for a cure for haemophilia and 
relieving the distress caused by this inherited disease should be prosecuted with 
all the vigour that we can. 

It was in 1996 at the Royal Free that we first realized that the other side of 
the coin of this great success in treating haemophilia was the fact that it was 
costing so much money. Peter Jones mentioned before tea that haemophilia is 'a 
bloody nuisance to everybody'. And indeed it is, and it has become an 
increasing nuisance in the sense that whilst recombinant factor VIII should 
obviously be the treatment of choice, particularly for children, so that they 
grow up without running the risk, or too great a risk, of other side-effects. So is 
this refined treatment that much more expensive? The fact remains that we were 
finding at the Royal Free in 1996 that we had patients side by side, one boy 
being treated with recombinant material and the boy next door not, simply 
because some of the purchasing authorities buying the services in the hospital 
were prepared to pay the extra cost and some were not. And when one looks at 
the enormous cost and the ever-increasing demand for money within the 
National Health Service, one realizes what a dreadful dilemma this is. 

What we did at the Royal Free in 1996 was to set up a task force, initiated 
by Martin Else, the Chief Executive of the hospital, which for the first time 
brought together all of the different disciplines to address the problem. In the 
past the Haemophilia Centre, important though it is, is when seen against the 
totality of the work going on in the hospital, a very small unit in a great 
enterprise. It was the first time that we brought together the legal people, the 
purchasing officers, all the different experts who were responsible in their 
individual way for moving things forward and we said to them, 'How are we 
going to persuade the funding bodies to give us the money, what techniques can 
we use, ranging from blackmail to appeal, to bursting into tears if you like, and 
secondly what proposals could we put forward to deal with this problem which 
was clearly going to get worse year by year and which was going to get ever 
more expensive'. The first part of the problem was successively resolved in the 
sense that in 1997 all of the young children at the Royal Free were on 
recombinant treatment. What's going to happen in 1998 and 1999, heaven 
knows! Possibly we shall still be having these arguments with the individual 
purchasing trusts as long as the concept that 'money follows patients' exists. But 
the more important outcome was that we were able to develop a detailed 
report to propose a national specialist commissioning advisory group to take 
this problem over as a national problem rather than it being regarded as a local 
problem for individual health authorities. And that report derived precisely 



78 



Haemophilia: Recent history 

from the fact that Katharine Dormandy's Trust gave us the opportunity, and the 
authority to get on with the job. I hope that the effect will be to lift this 
particular cost problem out of the domain of the individual purchasing trusts on 
to a more national basis. Whether that is a hope that has foundation remains to 
be seen, but I do very, very much pay tribute this afternoon to all of the people 
who have given so much to haemophiliacs, from Rosemary Biggs, Ethel 
Bidwell, Gwyn Macfarlane, Charles Rizza, Ted Tuddenham, Katharine 
Dormandy, Peter Kernoff, to all the other specialists in this area. 

Lee: Has anybody got some final comments that they are burning to 
contribute? I would like then to thank everybody. I speak for myself and say I 
don't think I have spent such an interesting afternoon for many a long day. I 
think it has been absolutely fascinating, and I think we should all be very 
grateful to the people who have travelled for very long distances. 

Tansey: On behalf of the Wellcome Trust, I would like to thank you all for 
participating in this afternoon's seminar. Speaking as a historian who came here 
knowing very little about haemophilia, it has been a great privilege listening to 
the accounts and I am convinced that the edited transcript of this meeting will 
be a valuable resource for future historians who will want to know about 
haemophilia at the end of the twentieth century. May I add my particular 
thanks to our Chairman, Christine Lee. We actually set this in motion only four 
months ago and had to put this meeting into our programme at very short 
notice. The driving force behind this meeting has come from Christine and I 
hope you will join me in thanking her. 



79 



Haemophilia: Recent history 

Appendix 

Classical Theory of Blood Clotting 1 

A three-stage process involving conversion of fibrinogen into fibrin following thrombin formation. 

1 . Platelet breakdown ► Thromboplastin 

Tissue damage ► Thromboplastin 

2. Prothrombin + Thromboplastin + Ca 2+ ► Thrombin 

3. Fibrinogen + Thrombin ► Fibrin 



A Present Day Theory 2 

Intrinsic pathway 

Kallikrein + foreign surface (collagen, platelets) 



Extrinsic pathway 

VII + III (Tissue thromboplastin) 



XII 



-> Activated XII 



XI 



i 



> Activated XI 

i 



IX ►Activated IX + VIII + platelet phospholipid + Ca 2t 

X 



i 



-> Activated X 4- 

I 



X 



Activated X + V + platelet phospholipid + Ca 2+ 



Common pathway 

XIII 



II (prothrombin) 



-> Activated II (prothrombin) 



I (Fibrinogen) 



Activated XIII 



-> Fibrin — — ► Fibrin clc 



Blood Coagulation Factors 



Factor 


Synonyms 


I 


Fibrinogen 


II 


Prothrombin 


III 


Tissue thromboplastin 


IV 


Calcium 


V 


Labile factor, proaccelcrin 


VII 


Stable factor, proconvertin 


VIII 


Antihaemophilic globulin, antihaemophilic factor A 


IX 


Christmas factor, antihaemophilic factor B 


X 


Stuart-Prower factor 


XI 


Plasma thromboplastin antecedent 


XII 


Hageman factor 


XIII 


Fibrin-stabilizing factor 



1 Adapted from Morawitz P. (1905) The chemistry of blood coagulation. 
Ergebnisse der Pbysiologie 4: 307—422. 

2 See for example O'Neil R. (1988) The blood. In Emslie-Smith D, Paterson C R, ScratcherdT, 
Read N W. (eds) Textbook of Physiology. Edinburgh: Churchill Livingstone, 35-36. 



79 



Glossary 



Haemophilia: Recent history 



Acquired immune deficiency syndrome 

(AIDS) - A condition linked to the 
retrovirus, human immunodeficiency 
virus (HIV-1). 

Anaphylactic reaction - An acute allergic 
response following injection of, or 
exposure to, a foreign protein or other 
substance, caused by the release of 
histamine or another vasoreactive 
substance. 

Antihaemophilic globulin (AHG) — 
See factor VIII. 

Arthropathy - The abnormality seen in 
joints of haemophiliacs after repeated 
episodes of spontaneous bleeding (e.g. 
secondary gross degeneration of the 
articular cartilage and bone). 

Bethesda unit - A unit used in the 

measurement of inhibitors arising in 
haemophiliacs (see note 83). 

Bleeding time — The time during which a 
small puncture or incised wound in the 
skin (made under controlled 
conditions) continues to bleed, 
normally less than ten minutes. 

Calcium-clotting time — The time for 
coagulation to occur when calcium 
chloride is added slowly to a mixture 
of saline and citrated plasma. With 
normal plasma the clotting time ranges 
from 90 to 250 seconds. 

Christmas disease - See haemophilia B. 

Christmas factor - See factor IX. 

Clotting time - A test of the clotting 
mechanism and the amount of 
thromboplastin formed. 

Creutzfeldt-Jakob disease (CJD) - 

A disease in which spongiform 
encephalopathy virus is implicated. 

Cross-correction — The haemophilic 
patient's plasma corrects, and is 
corrected by, the plasma of a known 
haemophiliac (see note 16). 



Cryoprecipitate - The plasma fraction 
that is obtained by freezing (— 20°C) 
and then thawing (4°C) normal human 
plasma. When frozen plasma is thawed 
slowly, the last proteins to dissolve 
include fibrinogen and factor VIII, 
and these make up the cryoprecipitate 
(see note 24). 

DDAVP — l-deamino-8-D-arginine 

vasopresssin (desmopressin). A synthetic 
analogue of the antidiuretic hormone 
L-arginine vasopressin, raises factor 
VIII levels when infused into healthy 
volunteers. 

Desmopressin — See DDAVP. 

Extrinsic (coagulation cascade) pathway - 

The pathway where tissue factors are 
required from outside the plasma in 
the process of coagulation (see 
Appendix) . 

Factor VII - A plasma coagulation factor 
intermediate in the clotting cascade 
(see Appendix). It normally circulates 
in an inactive form. 

Factor Vila - Activated factor VII. 

Contact with tissue extracts (released by 
tissue damage) converts factor VII to an 
active form, factor Vila. (The pathway 
is different from that involving factor 
VIII, so factor Vila can lead to clot 
formation in the absence of factor 
VIII.) 

Factor VIII (antihaemophilic globulin 

(AHG)) - A plasma coagulation factor 
whose inherited deficiency is 
responsible for classic haemophilia 
(lack of factor VIIIx) or von 
Willebrand's disease. 

Factor VIIIx - The coagulant moiety of 
the factor VIII complex, primarily 
deficient in classic haemophilia. 

Factor IX (Christmas factor) - A plasma 
coagulation factor that may be 
deficient on an inherited basis 
(haemophilia B). 

Fibrinogen — The precursor of fibrin in 
clot formation. 



Haemarthroses - Joint bleeds. 

Haematurea - Excretion of urine 
containing blood. 

Haemophilia - A hereditary bleeding 
disorder which affects the clotting of 
blood (see haemophilias A and B). 

Haemophilia A* - Factor VIII deficiency. 

Haemophilia B* - Factor IX deficiency 
(Christmas disease). 

Haemostasis - The arrest of haemorrhage. 

Hepatitis — Inflammation of the liver. 

Human immunodeficiency virus (HIV-1) 
— The retrovirus linked to AIDS, 
formerly AIDS-related virus. 

Inhibitor patients - Individuals who raise 
antibodies to factor VIII. 

Intrinsic (coagulation cascade) pathway - 

Intrinsic to plasma since all factors 
can be generated from plasma 
(see Appendix) . 

Kallikrein — The enzyme that releases 
bradykinin from the plasma protein 
kininogen. 

Platelet - Platelets are present in large 
numbers in blood and play an 
important role in blood clotting. 
Properties of adhesion and aggregation 
allow haemostasis when vascular 
endothelium is damaged, and also 
permit clotting 
(see Appendix) . 

Port-a-Cath - A device used when 
treatment into a vein is needed 
regularly. One end of the catheter lies 
in the right atrium of the heart. The 
other end, which provides access for 
injection of treatment, is either 
implanted under the skin of the chest 
wall or is taped to it. 



Prothrombin — A plasma protein yielding 
thrombin following activation by 
prothrombinase. 

Radiosynovectomy — A non-operative 
technique of injecting a 
radioactive isotope into the 
joint (see synoviorthrosis). 

Synovectomy — The excision of the 
synovial membrane that lines a joint 
or tendon sheath, used to treat chronic 
haemophilic arthropathy. It reduces 
but does not abolish further bleeds as 
it is rarely complete. 

Synoviorthrosis - The technique of using 
isotopes (e.g. radiocolloids) to produce 
fibrosis of the synovial membrane and 
hence reduce bleeding and subsequent 
damage. 

Thrombasthenia - An autosomally 
inherited haemorrhagic disease 
with unique abnormalities of 
platelet function. 

Thrombin — A proteolytic enzyme which 
induces clotting by the conversion of 
fibrinogen to fibrin. 

Thrombocytopenia - A deficiency 
of platelets often associated 
with haemorrhage. 

Thromboplastin generation test - A test 
for the efficiency with which 
thromboplastic activity appears in a 
mixture of coagulating blood 
components. 

von Willebrand's disease* - An inherited 
bleeding disease resulting from a 
deficiency or abnormality of the 
von Willebrand factor part of the 
plasma coagulation factor VIII 
complex. Clinical features include 
prolonged bleeding time and reduced 
platelet adhesiveness. 



♦Haemophilias A and B are Inherited in a sex- Linked manner, while von Tfillehrand's disease 
is inherited as an autosomal dominant condition. 



82 



Index: Subject 



Index : Subject 



acid-citrate-dextrose (ACD), 29 
accelerated degradation tests, 20, 21 
acquired immunodeficiency syndrome, 

see AIDS 
adrenaline, 10-11 

AHG, see antihaemophilic globulin 
AIDS, 64, 67, 80, see also human 
immunodeficiency virus 

as 'bystander effect', 68 

first cases in haemophiliacs, 26 

litigation, 63, 65-66 
albumin, 30, 75 
allergic reactions, 33, 80 
amputation, 18-19 
anaphylactic reactions, 14, 16, 80 
animal factor VIII concentrates, 13-15, 33, 

see also bovine antihaemophilic 

globulin 
antenatal diagnosis, 26, 27 
anticoagulants, 29 
antidiuretic hormone, 1 1 
antifibrinolytic drugs, 7 
antihaemophilic globulin (AHG), 43, 44, 

80, see also factor VIII 

animal, preparation, 48-51 

bovine, see bovine 

antihaemophilic globulin 

discovery, 4-5 

human, see factor VIII 

porcine, 7, 14, 74 
arthritis, haemophilic, 36 
arthropathy, haemophilic, 80, 81 
Australian antigen, 62 

Barcelona, Public Health 

Department, 23 
Baxter (UK), 25 
Bethesda unit, 25, 80 
bleeding 

abnormal, 4 

acute episodes, 6, 33, 35, 40 

post-traumatic, 5 

time, 6, 80, 81 

tissue destruction, 17 



blood, see also plasma 

bags, 25 

coagulation, see coagulation, blood 

donors, 24-25, 55-56, 70 

products, safety, 69-71 
Blood Products Laboratory, Elstree, 

19, 29, 30, 38, 59, 60 

blood factor purification, 73-74 

plasma fractionation methods, 19 
blood transfusion 

early, 6-7, 33, 40 

equipment, 28-29, 32-33 

safety, 69-71 

services, origins, 23 
Blood Transfusion Service, National, 

availability of blood products, 

24, 25, 33, 35-36, 38, 60 

safety of blood transfusion, 27, 70 

Booth Hall Children's Hospital, 

Manchester, 22, 23 

bovine antihaemophilic globulin 

(factor VIII), 7, 12 

clinical use, 14-16, 17 

preparation, 13-14, 61 

standards, 20-21 
brain, thromboplastic activity, 43-44 
Bristol Transfusion Centre, 30 
British Haemophilia Society, 7 
British Medical Journal, 45-47 
British Working Standard, 21 

calcium, 44 

calcium-clotting time, 80 

carriers, haemophilia, 4 

catch-22, 64 

catheters, see venous; Port-a-Caths 

centrifuges, 13 

cerebral haemorrhage, 24 

Chapel Hill, North Carolina, 

United States, 8 
children, 22 

blood transfusions, 33, 35 

HIV-positive, 27-28 



23 



83 



Index: Subject 



home treatment, 37 

hospitals, 27, 37 

recombinant factor VIII therapy, 74, 77 

self-treatment, 39 
Christmas disease (factor IX deficiency), 

11-12,46-47,80,81 

discovery, 6, 8, 9-10, 44-45, 46 

early treatment, 12 

factor IX concentrate therapy, 18-19 

origin of name, 46, 47 
Christmas factor, see factor IX 
chromosomes, autosomal, 80 
Churchill Hospital, Oxford, 12, 32, 61 
citrate-phosphate-dextrose with adenine 

(CPD-Ad), 29 
CJD, see Creutzfeldt-Jakob disease 
cloning, factor IX and VIII genes, 26, 74 
clotting 

blood, see coagulation, blood 

time, 5, 10, 80 
coagulation, blood, 43-44, 79 

cascade hypothesis, 45 

classical theory, 79 

extrinsic pathway, 43, 79, 80 

factors, 5, 79 

intrinsic pathway, 43, 79, 81 
Cohn's fibrinogen fraction, 12 
colour blindness, 7 

Commi tree on Safety of Medi ci nes, 69, 70-71 
concentrates, see also factor IX, concentrate; 
factor VIII, concentrate 

availability, 25, 29-30, 33, 35, 36, 38 

continuous infusions, 28-29 

freeze-dried, 7, 20, 25, 34 

heat treatment, 64 

HIV contamination, 25, 30 

home treatment, 34, 36 

imported from USA, 25, 30, 36, 

55-56, 63 

manufacture, 53, 54 

storage at home, 34, 35 

viral contamination, 26, 28, 62—71 
coronary thrombosis, 42 
coumarin plasma/serum, 43, 44 
Creutzfeldt-Jakob disease (CJD), 28, 40, 

66,80 

new variant (nvCJD), 63-64, 66 
Crookes Healthcare Ltd, 17 
cross-correction (mixing) experiments, 

6, 8, 9-10, 44-45, 80 



availability, 24, 25, 36 

discovery, 7, 35 

HIV contamination, 25 

home treatment, 33-34, 35, 36, 37, 39 
cystic fibrosis, 37 
cysts, haemophilic, 16-17, 32 

DDAVP (l-deamino-8-D-arginine 

vasopressin, desmopressin), 7, 10-11, 80 
dental extraction, 7, 14, 42 
Department of Health (and Social 

Security) 
(DHSS), 54, 64 

availability of blood products and, 30, 

59 

Haemophilia Register, 60 

HC-76/4, publication, 26 

Health Services Guidelines (93/30), 28 

MRC and, 59, 60 
desmopressin (DDAVP), 7, 10-11, 80 
developing countries, 57, 71 
diagnosis 

antenatal, 26, 27 

of haemophilia, 8-9, 10, 26-27 
drug users, 59 

economic aspects, haemophilia therapy, 35, 

75-77 
Edgware Transfusion Centre, 21 
Edinburgh, 11,59,60,62 
egg white, Timperley's, 41, 52, 53 
Elephant and Castle, Department of 

Health and Social Security, 59, 60 
Elstree, see Blood Products Laboratory, 

Elstree 
epistaxis (nose bleed), 43 
epsilon-aminocaproic acid, 7 
equipment, laboratory, 

availability, 13, 47, 61 

made of Meccano, 40, 41, 47 

transfusion/infusion, 28-29, 32-33 
European countries, 36 
exercise, factor VIII levels after, 1 1 
extrinsic pathway, see coagulation, blood 

factor V (labile factor), 42, 44, 45, 79 
factor VII, 42-43, 44, 79, 80 
activated (factor Vila), 26, 80 
recombinant, 28 



cryoprecipitate, 62, 71, 80 



84 



Index : Subject 



factor VIII, 79, 80, see also 

antihaemophilic globulin 

assays, 5, 20-22, 26, 45 

concentrate, 7, 12-17, see also bovine 

antihaemophilic globulin; porcine 

antihaemophilic globulin 

availability, 25, 29-30, 33, 38, 60 

continuous infusion, 28-29 

early clinical use, 14-16, 17, 24 

freeze-dried, 7, 20, 25 

human, 15, 16 

i ni ti al preparati on, 12-14, 44, 48-51 , 61 

manufacture, 15, 17, 53 

solubility, 17 

cryoprecipitate, see cryoprecipitate 

DDAVP therapy and, 1 1 

deficiency (haemophilia A), 75, 81 

discovery, 4-5, 12 

effects of adrenaline, 10-11 

effects of exercise, 1 1 

function, 45, 79 

gene cloning, 26—27, 74 

immunological detection, 5 

inhibitors (antibodies), see inhibitors, 
patients with 

long-term stability, 21 

purification, 71-74 

recombinant, 28, 67, 74 

availability, 62, 75 

economic aspects, 75-77 

guidelines on use, 74 

safety, 68, 70 

sequencing, 73, 74 

standards, 5, 20—21 

in von Willebrand's disease, 6,81 

von Willebrand's factor and, 72-73, 74 
factor VHI-related antigen, 72 
factor IX (Christmas factor), 79, 80 

assays, 19, 20-21, 45 

concentrate 

first clinical use, 18-19 

preparation, 19, 61 

deficiency, see Christmas disease 

gene cloning, 26 

purification, 73 

recombinant, 67, 75 
females 

haemophilic, 4, 17 

transmission of haemophilia, 4 
fetal blood sampling, 26 



fibrinogen, 44, 79, 80 

factor VIII separation, 12, 61, 74 

fraction, Cohn's, 12 

Food and Drug Administration (FDA), 63 

fractionation, plasma, see plasma, 
fractionation 

France, 66 

freeze-dried concentrate, 7, 25, 34 

freezers, 34, 35 

gangrene, 13, 18, 19 
Genentech Inc., 74 
genetic counselling, 56 
Glasgow Royal Infirmary, 43 
Government, 57, 62 

HIV infection and, 64-65 

safety of blood products and, 

30, 55-56, 67 
Great Ormond Street Hospital, 

London, 22, 39 
gun shot wound, patient with, 14, 16 

haemarthroses, 4, 8 1 
haematologists, 20, 24, 26 
haematuria, 43, 8 1 
haemophilia, 81 

A, 75, 81, see also factor VIII 

B, see Christmas disease 
care, 3-4, 22, 26, 38-39, 53 
carriers, 4 

diagnosis, 8-9, 10, 26-27 

distinction of two types, 

6, 8, 9-10, 44-45 

epidemiology, 31 

mild, 5,7, 10-11,40 

origin of name, 4 

treatment, see treatment of haemophilia 

von Willebrand's disease and, 5-6, 

72-73 
Haemophilia Centres, 6, 53, see also 

United 

Kingdom Haemophilia Centre 
Directors Organization; Katharine 
Dormandy Haemophilia Centre 

annual returns, 53-54 

comprehensive care, 38, 39 

concentrate supplies, 38 

Haemophilia Society and, 56 

three-tier system, 26 

two-tier system, 28 



85 



Index: Subject 



Haemophilia Society, 23, 26, 47, 54-56, 58 

beginnings, 7, 22, 41, 54-55 

HIV infection and, 56, 65, 66 

lobbying function, 55-56, 65, 66 

Manchester meeting, 27 

premises, 54, 55 
haemorrhoid surgery, 19 
haemostasis, 41, 81 
Hammersmith Hospital, London, 

44, 45-46 
Health Services Guidelines (93/30), see 

Department of Health 
heart failure, 24, 35 
heat treatment, 64 
hepatitis, 21, 40, 56, 62-63, 81 

A, 28, 69, 81 

B, 62-63, 69, 70, 81 

C, 28, 63, 66, 69, 70, 81 
non-A, non-B, 63, 69 
prevention of transmission, 64 

hip fracture, 17 

HIV, see human immunodeficiency virus 

home treatment, 33-35, 36-38, 39, 63 

availability of supplies for, 35, 36 

concentrate storage, 34, 35 

resistance to, 36 
hospitals, children's, 27, 37 
human factor VIII concentrate, 15, 16 
human immunodeficiency virus (HIV), 

63-68, 81, see also AIDS 

contaminated blood products, 25, 30, 

70-71 

infection, 40, 67-68 

Haemophilia Society and, 56, 65, 66 

litigation, 63, 65-66 

recompense for, 65 

in Scotland, 59, 65 

surgery in, 30-31, 32 

-positive children, 27-28 

television advertisements, 27 

testing, 27, 70 
hypoprothromboplastinogenaemia, 47 
hypothalamic-pituitary axis, 1 1 



intrinsic pathway, see coagulation, blood 

Japan, 66 

jaundice, 67, see also hepatitis 
John Bell and Croyden, London, 40 
joint bleeds (haemarthroses), 4, 81 

kallikrein, 8 1 

Katharine Dormandy Haemophilia 

Centre, 34, 58 
Katharine Dormandy Trust, 76, 77 

labile factor, see factor V 

Lawn Road Hospital, Hampstead, 34, 58 

life expectancy, 31, 67 

Lister Institute, Elstree, 19, see also Blood 

Products Laboratory, Elstree 
litigation, for HIV infection, 63, 65-66 
Lord Mayor Treloar Hospital and 

College, Alton, Hampshire 67 

Macfarlane Trust, 3, 28, 65 
Manchester, 22, 23, 24-25, 27, 60 
Manchester Royal Infirmary (MRI), 23, 

24, 25, 37 
Maws & Son Ltd, 15, 17 
Meccano, see equipment 
Medical Research Council (MRC), 52, 53, 

58-60, 61, 62, 73 

Blood Coagulation Research Unit, 

Oxford, 12, 58, 61 

Blood Products Laboratory, Elstree, 29, 

59 

Blood Transfusion Research 

Committee, 58-59 

Central Workshops, 61 

Haemophilia Committee, 58 

Haemophilia Register, 59-60, 62 

Park Crescent headquarters, 59, 60 
Ministry of Health, 52, 53, see also DHSS 
monoclonal antibodies, 73—74 
MRC, see Medical Research Council 



infusions, continuous, 28-29 
inhibitors, patients with, 25, 71, 75, 81 

factor Vila therapy, 26, 28 

orthopaedic surgery, 32 
International Haemophilia Society, 7 
International Society of Thrombosis and 

Haemostasis Meeting, 73 



National Blood Authority, 60 

National Blood Transfusion Service, see 

Blood Transfusion Service, National 
National Health Service, 52, 77 
National Institute for Medical Research, 

Biologi cal Standards Di vi si on, 5, 20-21 , 61 
needles, 28-29, 33 



86 



Index : Subject 



New York Medical Center, 21 

Newcastle, 35, 39 

Norwich, patient from, 14, 16 

nose bleed (epistaxis), 43 

Nuffield Orthopaedic Hospital, Oxford, 

3 
nurse, haemophilia, 37-38 
nvCJD, see new variant CJD 

orthopaedic surgery, elective, 31-32 

osteomyelitis, 18 

Oxford, 3, 9-10, 39, 53 

blood coagulation studies, 41-42, 43, 
44-45, 58, 61 

Blood Transfusion Centre, 13, 33, 70 
factor VIII concentrate, 13-15 
Haemophilic Unit, 30, 31-32 
referral of patients to, 17, 18-19 

parents 

HIV-positive children, 27-28 

home treatment and, 36, 37, 39 

views of one, 38-40 
parvovirus, 26, 63 

patients, haemophilic, 22, see also children; 
parents 

independence, 39-40 

life expectancy, 3 1 , 67 

plasma donation by, 8 

recollections of, 40—41 
peptic ulceration, 15, 17 
plasma 

cross-correction (mixing) experiments, 

6, 8, 9-10, 44-45, 80 

donation by haemophiliacs, 8 

fractionation, 4-5, 12, 38 

facilities, 30, 54, 59, 61, 62 

methods, 19, 44 

fresh-frozen, 24, 33, 35 

snap-frozen, 24 

supplies, 60 
plastics, 13, 15 
platelets, 43, 44, 81, see also 
thrombocytopenia 

clumping, 16, 72, 74 
porcine antihaemophilic globulin (AHG, 

factor VIII), 7, 14,74 
Port-a-Caths, 28-29, 81 
pregnancy, termination, 26 
prothrombin, 43, 79, 81 

sequencing, 73 



time, 4, 42, 43 



Quick's one-stage prothrombin time test, 

42 



Radcliffe Infirmary, Oxford, 3, 9, 61 

radiosynovectomy, 29, 31, 81 

recombinant products, see also factor VIII, 
recombinant 
safety, 68, 70, 74-75 

recompense, campaign for, 65 

Red Cross, 23, 25 

Register, Haemophilia, 59-60, 62 

Registry, Haemophilia, 47, 53-54 

rehabilitation, after orthopaedic surgery, 
32 

Royal Free Hospital, London, 17, 22, 
36-37, 39, 73, see also Lawn Road 
Hospital, Hampstead; Katharine 
Dormandy Haemophilia Centre 
recombinant factor therapy, 75, 77 

Royal London Hospital, 17, 37-38 

Russell's viper venom (Stypven), 6, 39, 40 

St Bartholomew's Hospital (Bart's), 

London, 40, 41, 76 
St Mary's Hospital, London, 29 
St Thomas' Hospital, London, 4, 22 
schooling, 37 
Scotland, 59, 60, 62, 65 
SEAC, see Spongiform Encephalopathy 

Advisory Group 
sheep, 16 

slaughterhouse, 13, 47 
Spanish Civil War, 23 
Speywood Laboratories, 74 
spongiform encephalopathy, 63, see also 

Creutzfeldt-Jakob disease 
Spongiform Encephalopathy Advisory 

Group (SEAC), 66, 69 
standards, reference, 20-22, 25, 61 

factor VIII, 5, 20-21 
stars, seeing, 16, 74 
sterilization, 14 

Stypven, see Russell's viper venom 
surgery 

elective orthopaedic, 31—32 

HIV-infected patients, 30-31, 32 

manufacture of factor VIII for, 15-16, 

19 
synovectomy, 29, 31,81 



87 



Index: Subject 



synoviorthrosis, 31,81 
synovitis, chronic, 31 
syringes, 33 

termination of pregnancy, 26 
thrombasthenia, 44, 81 
thrombin, 4, 43, 44, 79, 81 
thrombocytopenia, 11, 16, 81 
thromboplastin, 44, 79 

generation test, 6, 8-9, 43-44, 45, 

46,81 

time, partial, 8 
thrombosis, 41, 42 
Timperley's egg white, 41, 52, 53 
tongue, bleeding, 46 
tooth extraction, 7, 14, 42 
transport, for disabled, 55 
travel, by patients, 39-40, 57 
treatment of haemophilia, see also surgery 

cryoprecipitate, 24-25 

early, 6-7, 12, 32-33, 39, 40-41, 

52-53 

economic aspects, 35, 75—77 

factor IX concentrate, 18-19 

factor VIII concentrate, 14-16, 17, 24 

historical sequence, 28-29 

home, see home treatment 

mild disease, 10-11 

recommended, 67, 75 

resistance to, 35-36, 76 

side-effects, 4, 62-71, 74 
Tuta (Australia), 25 



United Kingdom Haemophilia Centre 
Directors Organization (UKHCDO), 
52-53, 62 

beginnings, 28, 47, 52-53 
guidelines on treatment, 75 
HIV infection and, 64, 65-66 
on safety of blood products, 67 

United States of America, 73 

concentrates from, 25, 30, 36, 55-56, 63 
diagnostic tests, 8 

vasopressin, 1 1 

venepuncture, 18, 43 

venous catheters, in-dwelling, 28-29 

Victoria, Queen of England, and 

haemophilia, 4 
viruses, see ^/wkimanimmunodefi ci encyvirus 

contami rati on of concentrates, 26, 28, 62-71 
volunteerism, 55, 56, 57 
von Willebrand's disease, 5—6, 23, 81 

haemophilia and, 5-6, 72-73 

treatment, 7, 1 1 
von Willebrand's factor, 72-73, 74, 81 

Wellcome Foundation, 13 
Wellcome Trust, 78 
WHO, see World Health Organization 
Wilkinson Committee, 58 

WorldFederationof Hemophilia, 40, 47, 

56-57 

beginnings, 7, 57 

safety of blood products, 66, 71 
World Health Organization (WHO) 

factor VIII availability, 30 

international standards, 20, 21 



88 



Index: Name 



Index: Name 



Addis, T, 4 
Alexander, B, 6 
Allain, Jean-Pierre, 66 



Evans, David, 22-29, 30, 37, 47, 63 



Fildes, Paul (later Sir) 4 



Bangham, Derek, 20-21, 61 

Bergsagel, Danny, 14 

Bidwell, Ethel, 7, 11, 12, 13-14, 15, 16, 
18, 19, 20, 41-42, 47, 48-51, 61, 77 

Biggs, Rosemary, 3, 6, 7, 8, 9, 10, 14, 16, 
18, 19, 20, 21, 36, 41-42, 43, 44, 46, 
47, 54, 58, 59, 67, 70, 73, 75, 77 

Blomback, M, 7 

Bloom, Arthur, 71-72, 73 

Blumberg, Baruch Samuel, 62 

Booth, Sir Christopher, 45-46 

Brinkhous, K N, 8 

Britten, Peggy, 57, 58 

Brozovi_, Milica, 21 

Bull, Sir Graham, 46 

Bulloch, W, 4 



Cash, John, 7, 11,62 

Christie, Daphne, 6, 19, 20, 21, 29, 31, 

32, 36, 43, 57, 59, 61, 65, 66, 70 
Christmas, Stephen, 9, 10, 44, 46-47 
Cohn, EJ, 12 
Colvin, Brian, 17, 37-38 

Dacie, John, 10, 44, 46 
Dalrymple-Champneys, Sir Weldon, 

52, 54 
Denson, Ken, 20 
Dike, Angela, 70 
Dike, Ross, 12, 14, 19, 47, 

48-51,61,70 
Dodsworth, Helen, 29-30, 59, 60 
Doll, Sir Richard, 68 
Dormandy, Katharine, 34-35, 37, 38, 

39, 57, 58, 73, 76, 77 
Douglas, Stuart, 6, 9-11, 41-45, 62 
Duesberg, Peter, 68 
Duran-Jorda, Frederico (Frederick), 

23-24 
Duthie, Robert, 18, 30-32 

Else, Martin, 77 



Goldstein, R, 6 
Goodall, Alison, 73 
Graham, J B, 5, 8 
Grant, Jean, 33 

Haldane, J B S, 7 

Hardisty, Roger, 22, 39 

Heath, David, 74 

Hill, Graham, 55 

Hopff, F, 4 

Howarth, Sheila, 58, 60, 62 

Hoyer, Leon, 73 



Ingram, Ilsley, 4-8, 9, 10, 11, 12, 15, 16, 

17, 22-23, 39, 47, 58 



Jenkins, George, 37 
Johnson, Alan, 9,21,74 
Jones, Peter, 15, 17, 22, 27, 35-36, 
37, 39, 57, 62-67, 70-71, 75, 76 



Kekwick, Ralph, 7, 19, 20, 24 
Kernoff, Peter, 34, 35, 77 



Lane, S, 6 

Larrieu, M J, 6 

Lee, Christine, 3-4, 8, 9, 11, 12, 13, 
14-15, 16, 18,20,22,31,32,33, 
34, 38, 39, 41, 46-47, 53, 54, 56, 
57, 58, 60, 62, 65, 66, 67, 68, 71, 
75-76, 77-78 

Lewis, J H, 5 

Macfarlane, Gwyn, 3, 5, 6, 7, 9, 10, 12, 
13, 14, 15, 18, 20, 38, 40, 41-42, 45, 
46,47,52,58,59,61,70,76,77 

Mackay, M E, 19 

McKee, P A, 72 

Magnusson, Stephan, 73 



89 



Index: Name 



Major, Rt Hon John, 65 

Mannucci, P M, 7, 10, 11 

Matthews, James, 7, 16, 32-33, 34 

Merskey, Clarence, 5, 9-10, 44, 45 

Miller, Riva, 36-37 

Minor, G R, 5-6 

Mollison, Patrick (Pat), 30, 58, 59 

O'Brien, John, 10 

Owen, David (later Lord), 55-56 

Owren, P A, 42 

Patek.AJ, 5 

Pavlovsky, A, 6, 10 

Pitney, W R (Bob), 10, 44, 46 

Pool, Judith (Judy), 7, 24, 35 

Poole, John, 9, 10,45 

Powell, A E, 72 

Quick, A J, 4, 42 

Ratnoff, O D, 5, 72 

Reynolds, Lois, 69 

Rizza, Charles (Charlie), 3, 7, 9, 10, 11, 
12, 16, 17, 18-19, 20, 31-32, 34, 37, 
38, 43, 52-54, 59, 60, 67-68, 7A, 77 

Schnabel, Frank, 57 
Shannon, A E, 7, 35 
Skegg, Joyce, 21 
Smallpeice, Victoria, 1 8 
Smith, Alan, 71 
Smith, Frank, 41, 52 
Soulier, J P, 6, 7 
Spooner, Rosemary, 37, 53-54 



Stockford, Victoria, 55 
Stratton, Frederick (Fred), 24, 25 

Tanner, Alan, 38-39, 40, 54-56, 57, 66 

Tansey, E M (Tilli), 3, 4, 10, 69, 78 

Taylor, F H L, 5 

Teitle, Jerry, 46 

Thatcher, Margaret (later Dame), 65 

Timperley, WA, 41 

Tovey, Geoffrey, 30 

Treves, F, 4, 17 

Trueta, Joseph, 18, 23 

Tuddenham, Edward (Ted), 34-35, 37, 

67, 71-75, 77 
Tyrrell, David, 66, 69-70 

Vallet, Leon, 19 

Wagner, R H, 8, 72 
Walsh, P N, 7 
Walton, Peter, 20 
Watson, Irene, 55 
Watson-Williams, Dr, 24 
Waiters, David, 56, 65 
Weatherall, Sir David, 71 
Welch, Clifford, 36, 40-41, 

52, 75, 76-77 
Whitby, Sir Lionel, 22 
Wilkinson, John, 23, 52, 58 
Willebrand, E A von, 5-6 
Witts, Leslie, 43 
Wolf, Peter, 7, 24 
Wright, Irving, 5 

Zimmerman, T S, 5, 72 



90